Rv2699c Still unknown · low auto-curated

H37Rv Rv2699c · MTBC0 mtbc0_002873 · 100 aa · 3037078–3037380 MTBC0 (-) · RefSeq NP_217215.1

Annotation: from legacy to revised

Legacy (H37Rv / Mycobrowser)	hypothetical protein
MTBC0 PGAP re-annotation	DUF4193 domain-containing protein
Revised (this work)	Conserved hypothetical protein; DUF domain(s) DUF4193. Function unknown.
Functional category (TubercuList)	conserved hypotheticals

Curation note: P16.14 TrEMBL-name audit (2026-07-11): UniProt TrEMBL name 'dUTPase' NOT corroborated and contradicted -- eggNOG assigns DUF4193 and Foldseek shows no dUTPase; the annotated dut (dUTPase) is the near neighbour Rv2697c, so the name is a mis-propagation. Kept dark. NB a real, important gene: essential (DeJesus ES), highly vulnerable (VI -6.8), DUF4193, conserved to Actinomycetia -- function still unknown.

Auto-curated: this verdict and function were generated by rules from PGAP + Pfam + Foldseek and have not been hand-reviewed.

In the literature (TB corpus sweep) never studied

No TB publication mentions this locus tag in its title or abstract (sweep of a ~330k-abstract PubMed TB corpus). This gene is genuinely unstudied: its darkness reflects absence of investigation, not failure of investigation.

An antigen status or a virulence phenotype is NOT a molecular function: the verdict stays unchanged. This layer adds the missing context, it does not requalify the gene. This distinguishes a gene that is dark because nobody has looked from one that is dark despite having been studied. Source: PubMed (whole), MULTI-ALIAS sweep of title+abstract: the H37Rv locus tag AND every ortholog identifier (M. bovis Mb…, M. marinum MMAR_…, M. smegmatis MSMEG_…, M. leprae ML…, M. abscessus MAB_…), each hit VERIFIED against the abstract text (word-boundary regex). phase73, 2026-07-13.

Intrinsic disorder (sequence + structure) highly disordered

Predicted disorder	59% of residues (metapredict) · mean AlphaFold pLDDT 78.4
Disordered regions	1 IDR(s), longest 59 aa [0-59]

sequence-based disorder is high but AlphaFold folds it confidently (pLDDT>=70): treat the disorder call with caution (possible metapredict over-call)

A property (biophysics), not a function. No LLPS/condensate claim is made from disorder alone. Verdict unchanged. Source: metapredict v3 (Emenecker/Holehouse) per-residue disorder + AlphaFold mean pLDDT (annotation_mtbc P16.13).

Binding-pocket screen (P2Rank, geometric prediction) detector blind at this length

Pockets found	0
Model length screened	100 aa

Read with care. This protein (100 aa) is below the size where this detector has meaningful power: on proven enzymes, only 3.8% (1/26) under 200 aa reach the P2Rank confidence threshold, versus 60.5% (75/124) above it (P16.3b calibration, negative control EsxA/EsxB-scale panel). A negative or weak pocket result here should NOT be read as evidence against a ligand-binding role -- the test essentially has no power at this length, not that the protein lacks a site. P16.3e, calibration phase72b_pocket_calibration.py, 2026-08-03.

CRISPRi vulnerability

Vulnerability index -6.76 (95% CI -7.55 to -5.94). A more negative index = more vulnerable to knockdown (better drug-target quality); indicative threshold VI ≤ -6 = highly vulnerable.

Quantitative CRISPRi knockdown, graded (finer than binary Tn-seq essentiality). Source: CRISPRi vulnerability index (Bosch 2021, pebble.rockefeller.edu).

Legacy record & comparison (Mycobrowser)

Mycobrowser function	Function unknown

The legacy Mycobrowser record is shown for verification. Mycobrowser is no longer maintained; its EC numbers predate recent nomenclature revisions, so a class change usually reflects re-numbering, not a conflict.

Orthologues (reciprocal best hits across mycobacteria)

M. bovis	`Mb2718c` · 100.0% identity
M. leprae	`ML1026` · 96.0% identity
M. marinum	`MMAR_2015` · 96.0% identity
M. smegmatis	`MSMEG_2763` · 95.0% identity
M. orygis	`RJtmp_002783` · 99.0% identity
M. abscessus	`MAB_3005c` · 89.0% identity

Reciprocal-best-hit orthologues (DIAMOND) against the Mycobrowser reference proteomes. A missing species is informative: e.g. a gene absent from M. leprae was likely lost in its reductive genome evolution. Locus tags link to Mycobrowser.

Curated reference (UniProt)

UniProt	`I6YA17` TrEMBL · unreviewed · Evidence at protein level
UniProt name	dUTPase

Functional vocabulary (eggNOG-mapper, orthology transfer)

COG category	`S` Function unknown
eggNOG description	Domain of unknown function (DUF4193)
Orthologous group	`2ATJW`

Orthology-based transfer (eggNOG 5.0.2, diamond). EC/KO/GO/CAZy are computed annotations, not manual curation; cross-check against the primary literature before treating a specific reaction as established.

Conservation & selection (intra-MTBC, 145 209 strains)

pN/pS	n/a
Polymorphic sites (≥ 0.1% of strains)	0 synonymous, 1 missense, 0 nonsense, 0 frameshift

pN/pS from segregating SNPs (singletons removed) normalised by possible sites. Low pN/pS = purifying selection (a strong signal that a "hypothetical" is a real, constrained gene). A high pN/pS is ambiguous: relaxed constraint or positive selection (drug resistance, antigenic variation) inflate it; e.g. rpoB/katG/pncA score high here for resistance, not loss of function. A clonal disruption (one allele over a clade) suggests lineage pseudogenisation; a convergent one (many independent alleles) is typical of resistance loss-of-function.

Outgroup conservation (beyond the MTBC) Actinomycetia

Genus-wide presence (~53 non-MTBC Mycobacterium)	present in 53/53 (100%) · mean identity 97.6% · 4/4 closest MTBAP relatives conserved across the genus (present in 53/53 non-MTBC Mycobacterium genomes, incl. distant relatives) — an ancient core gene predating the genus radiation
Phylostratum (deepest detected homolog)	MTBC-specific → Mycobacterium → Mycobacteriaceae → Corynebacteriales → Actinomycetia → Bacteria detected in 11/13 non-Mycobacterium reference genomes (down to Actinomycetia) · mean identity 72.2% detected across the class Actinomycetia (beyond Corynebacteriales) but not outside the phylum — an Actinobacteria-level ancient gene

Two orthogonal outgroup signals. M. canettii (the immediate outgroup) gives a deep-divergence dN/dS (a low value confirms a constrained, real gene; shown as confident only at ≥8 substitutions, else flagged low-power). Genus-wide presence/absence (tblastn vs assembled non-MTBC genomes) places the gene on the ancient-core ↔ MTBC-specific axis: a gene absent even from the closest MTBAP relatives is a candidate MTBC-specific innovation (possible host-adaptation factor, to confirm by synteny). The phylostratum extends that axis outside the genus (tblastn vs 13 reference genomes spanning Mycobacteriaceae → Corynebacteriales → Actinomycetia → outside the phylum): it is the deepest clade in which a homolog is still detected, i.e. a proxy for gene age. Read it with the null model in mind: a shallow (young) stratum can also reflect homology-detection failure for short or fast-evolving ORFs, so it is a descriptive axis, not a proof of novelty.

Essentiality (transposon mutagenesis) essential

DeJesus 2017 call	ES · essential
What the call means	essential: insertions absent across the whole ORF
TA sites (Himar1)	4 in the ORF — 4 in the essential state, 0 growth-defect, 0 non-essential, 0 growth-advantage. Saturation 0.000, mean read count 0. A region of the protein devoid of TA sites is invisible to this assay: nothing can be inferred about it, in either direction.
Caveat	Statistically thin call: only 4 TA (Himar1) sites in the whole ORF (atlas median 13; genes under 300 nt typically have very few). A DeJesus 2017 call built on so few independent observations is less robust than the same call on a longer gene, in either direction. Cross-check against the CRISPRi vulnerability index (independent of TA-site density) and, if this gene overlaps a neighbour (see Genomic-neighbour overlap section below), verify how many of its TA sites actually fall inside its own ORF. (P20.3)

Genome-wide Himar1 transposon essentiality in H37Rv (DeJesus 2017). An essential call (ES/ESD/GD) is strong, independent evidence that a "hypothetical" locus encodes a functional, selectively required gene — orthogonal to intra-species conservation.

Chemical-genetic target & druggability (PROSPECT) hypomorph tool strain

This gene is part of the PROSPECT collection of TetON transcriptional-knockdown (hypomorph) strains of essential M. tuberculosis genes, built as a sensitised background for chemical-genetic mechanism-of-action deconvolution. Being in the panel means the gene is an essential / vulnerable target for which a validated knockdown tool strain exists.

Hypomorph strain	Rv2699c_TetOn10.1 (TetON promoter 10)
Baseline knockdown fitness	4.3 median doublings (across 1 screen pool(s)) — fewer doublings = stronger growth defect on knockdown
Used in target deconvolution	no (Excluded - not in all screening waves)

Panel membership reflects essentiality/vulnerability and the availability of a genetic tool, not a specific molecular function; it never changes the verdict here. Source: Bond AN et al., Nat Commun 2025;16:9673 (doi:10.1038/s41467-025-64662-x); PROSPECT chemical-genetic platform.

Proteomics (mass spectrometry) detected

MS detection	detected in 15 of 16 independent MS datasets
Integrated abundance	1021.0 ppm · rank 225/3519 (93.6th percentile)

Detection by mass spectrometry is direct, experimental evidence that the protein product exists — orthogonal to sequence conservation and to Tn-seq essentiality, and especially decisive for a "hypothetical" locus. Reproducible detection across several independent datasets (PaxDb) makes the existence claim robust; the integrated abundance places the protein in the proteome's dynamic range.

Physico-chemical properties (computed, ProtParam)

Length	100 aa
Molecular weight	10.9 kDa
Theoretical pI	4.25
GRAVY	-0.52 (hydrophilic)
Aliphatic index	68.3
Aromaticity	0.04
Instability index	66.7 (unstable)

Computed from the ancestral MTBC0 sequence with the ExPASy ProtParam method (Biopython). Descriptive biophysical context: a positive GRAVY flags a hydrophobic (often membrane) protein, a high instability index (>40) predicts a short in-vitro half-life, an extreme pI hints at compartment or binding partner.

Domains (Pfam, hmmscan --cut_ga)

Pfam	Accession	i-Evalue	Residues	Description
`DUF4193`	PF13834.12	1.4e-45	1–99	Domain of unknown function (DUF4193)

Genomic context (neighbours & predicted operon)

Upstream (5' on genome)	`Rv2698` (+ strand, 4 bp gap)
Downstream (3' on genome)	`Rv2700` (+ strand, 237 bp gap)

Neighbours from the H37Rv annotation (- strand). The operon is predicted by co-directional intergenic distance (same strand, gaps ≤50 bp) — a transcription-unit hypothesis, not a mapped TSS. For a "hypothetical", co-transcription with a characterised operon is a concrete functional lead (complements the STRING neighborhood channel below).

Transcriptional regulation (signed TRN: ChIP-seq + TFOE)

Regulated by (1 TF)	`mmpR5` (activates)

Regulatory edges from the ISB signed transcriptional regulatory network (TF ChIP-seq binding, Minch 2015 + TF-overexpression response, Rustad 2014). An edge is regulatory evidence (binding and/or expression change), not necessarily direct. For a "hypothetical", membership in a known regulon (e.g. DosR dormancy, PhoP virulence) is a strong physiological-context lead.

Functional interaction network (STRING v12, guilt-by-association)

Explore full network →

Node colour = verdict, dashed = hypothetical; edge colour = evidence (green experimental, orange genomic-context, grey co-expression), width ∝ score. Click a partner to open its page; "Explore full network" to walk the graph.

Closest characterised functional partner: rbpA (RNA polymerase-binding protein RbpA), high confidence from genomic context alone (score 784 excluding text-mining). This association is the citable seed of a function hypothesis for this hypothetical protein.

Partner	Product	Score	No text-mining	Channels (≥400)
`Rv2050` rbpA	RNA polymerase-binding protein RbpA	783	784 ctx	cooccurence:773
`Rv1830`	HTH-type transcriptional regulator	772	772 ctx	cooccurence:771
`Rv1423` whiA	transcriptional regulator WhiA	766	766 ctx	cooccurence:766
`Rv2239c` hyp	hypothetical protein	751	752 ctx	cooccurence:751
`Rv2256c` hyp	hypothetical protein	751	752 ctx	cooccurence:750
`Rv2700` cei hyp	hypothetical protein	745	746 ctx	neighborhood:746
`Rv2731` hyp	hypothetical protein	739	739 ctx	cooccurence:738
`Rv2708c` hyp	hypothetical protein	724	725 ctx	cooccurence:722
`Rv2206`	transmembrane protein	722	723 ctx	cooccurence:722
`Rv2745c` clgR	transcriptional regulator ClgR	714	715 ctx	cooccurence:711
`Rv1390` rpoZ	DNA-directed RNA polymerase subunit omega	711	712 ctx	cooccurence:711
`Rv2413c` hyp	hypothetical protein	706	706 ctx	cooccurence:706
`Rv3195` hyp	hypothetical protein	701	701 ctx	cooccurence:701
`Rv2219`	transmembrane protein	696	696 ctx	cooccurence:693
`Rv1440` secG	protein-export membrane protein SecG	688	688 ctx	cooccurence:687

STRING combines evidence channels (neighborhood, fusion, cooccurrence, coexpression, experimental, database, text-mining) into a 0–1000 score. The ctx badge marks edges carried by the genomic-context channels (conserved neighborhood, fusion, phylogenetic co-occurrence), which are independent of orthology and structure and the strongest signal for an unknown gene. The exp badge marks an experimentally-supported partner (measured interaction, experimental/database channel ≥400) as opposed to a purely predicted one — but note that the M. tuberculosis experimental interactome is dominated by a noisy bacterial-two-hybrid screen, so a strong measured link that contradicts the operon/localisation context is likely a false positive. The no text-mining column recomputes the score from data alone, so a link that does not depend on the literature is visible. Association is a function hypothesis, not proof: corroborate with the operon context and the primary literature before assigning a function.

Evidence

Legacy H37Rv annotation: hypothetical protein
MTBC0 PGAP product: DUF4193 domain-containing protein
Pfam (hmmscan --cut_ga): DUF4193 PF13834.12 (E=1e-45)
(auto-curated by rules from PGAP + Pfam + Foldseek; not hand-reviewed)

Sources

Ancestral sequence & coordinates: Harrison LB et al. (2024), An imputed ancestral reference genome for the MTBC, doi:10.1101/2023.09.07.556366
Product annotation: NCBI PGAP on MTBC0; legacy from H37Rv NC_000962.3 (RefSeq NP_217215.1)
Domains: Pfam-A via hmmscan --cut_ga — DUF4193 (PF13834.12)
Sequence-level signal: ESM Atlas (EvolutionaryScale × BioHub) — exploratory
Controlled vocabulary: eggNOG-mapper 2.1.12 (Cantalapiedra et al. 2021, doi:10.1093/molbev/msab293), eggNOG 5.0 DB (Huerta-Cepas et al. 2019) — OG 2ATJW
Curated reference: UniProt I6YA17 (TrEMBL, unreviewed; Evidence at protein level)
Intra-MTBC selection: pN/pS and disruption from SPDI variants of 145 209 MTBC strains (this work, local collection vs H37Rv NC_000962.3)
Genome-wide structure: AlphaFold DB model (Jumper et al. 2021, doi:10.1038/s41586-021-03819-2; Varadi et al. 2024, doi:10.1093/nar/gkad1011) searched vs PDB with Foldseek (mean pLDDT 78.4)
Interaction network: STRING v12.0 (Szklarczyk et al. 2023, doi:10.1093/nar/gkac1000), taxon 83332, CC-BY 4.0 — 49 functional partner(s); context anchor rbpA
Essentiality: genome-wide transposon mutagenesis in H37Rv — DeJesus et al. 2017 (mBio, doi:10.1128/mBio.02133-16, CC BY)
Proteomics: integrated mass-spectrometry abundance from PaxDb 5.0 (Huang et al. 2023, doi:10.1016/j.mcpro.2023.100640), taxon 83332 — weighted average of 16 datasets, incl. Schubert et al. 2013 (doi:10.1016/j.chom.2013.04.008) and Albrethsen et al. 2013 (doi:10.1074/mcp.M112.018846)
Functional category: TubercuList scheme (Cole et al. 1998, doi:10.1038/31159), via Mycobrowser (Kapopoulou et al. 2011, doi:10.1016/j.tube.2010.09.006)
Orthologues: reciprocal best hits (DIAMOND, Buchfink et al. 2021, doi:10.1038/s41592-021-01101-x) against Mycobrowser release 5 reference proteomes
Genomic context / operon: H37Rv annotation; operon predicted by co-directional intergenic distance (Salgado et al. 2000, doi:10.1073/pnas.030539397)
Transcriptional regulation: ISB signed TRN — TF ChIP-seq (Minch et al. 2015, doi:10.1038/ncomms6829) + TF overexpression (Rustad et al. 2014, doi:10.1186/gb-2014-15-11-502)
Physico-chemical properties: ExPASy ProtParam method via Biopython (Gasteiger et al. 2005), computed from the MTBC0 sequence
Primary literature: none located yet; annotation rests on the domain/homology sources above.

Ancestral MTBC0 protein sequence

>mtbc0_002873|Rv2699c|
MPTDYDAPRRTETDDVSEDSLEELKARRNEAASAVVDVDESESAESFELPGADLSGEELSVRVVPKQADEFTCSSCFLVQHRSRLASEKNGVMICTDCAA

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Genomic neighbourhood (genome browser)