Rv2767c Family assigned · low

Annotation: from legacy to revised

Curation note: 2026-09-09 (P46.4): the served sentence asserted co-transcription as a fact while this record's own per-claim operon check (phase201, P40.9) returns CONTREDIT — Roback et al. 2007 places the cited neighbour in another transcript and REMap 2016 does not cover the pair. The claim is not refuted but UNSUPPORTED, and the sentence now says so: a lone Roback disagreement is weak evidence (that map agrees with only 5 of our 12 operon-based requalifications, one-sided binomial p = 0.54 against the base rate over CO-DIRECTIONAL adjacent pairs, and REMap agrees 9 times out of 10 at p = 0.12, no better than chance either). Verdict and confidence are unchanged: they already read 'contextual candidate, molecular role not established'. 2026-10-09 (P60.13): the two p-values in the sentence above were corrected. The earlier p = 0.19 and p = 0.005 were computed against a null that counted opposite-strand adjacent pairs, which cannot form a transcription unit at all and which neither map calls; conditioned on the co-directional pairs that the twelve requalifications actually concern, the two maps read p = 0.54 and p = 0.12, so REMap's agreement is no longer distinguishable from chance. The reading of this record does not change: the co-transcription claim stays UNSUPPORTED rather than refuted, and verdict, confidence and function_revised wording are untouched beyond the two figures.

In the literature (TB corpus sweep) named only in full text

No publication mentions this gene in its title or abstract — not under its H37Rv locus tag, not under its gene name, and not under any ortholog identifier. Its annotation rests on sequence/structure evidence, with no primary study behind it.

Scope of the sweep: What was actually swept: the H37Rv locus tag and the ortholog locus tags (M. bovis Mb…, M. marinum MMAR_…, M. smegmatis MSMEG_…, M. leprae ML…, M. abscessus MAB_…), plus the gene name where one exists. NOT swept: protein and enzyme names, including family shorthands such as Ldt(Mt4) or VapC28, and their orthographic variants. An absent locus-tag mention is therefore evidence about the TAG, and only indirect evidence about the protein (P18.14).

This layer CITES the literature and adds context; it does not change the verdict or the function stated elsewhere in this fiche. This distinguishes a gene that is dark because nobody has looked from one that is dark despite having been studied. Source: PubMed (whole): H37Rv locus tag + GENE NAME + ortholog identifiers (Mb…, MMAR_…, MSMEG_…, ML…, MAB_…), under a mycobacterial context filter; hits verified against the abstract text. Species-context counts distinguish M. tuberculosis literature from literature on other mycobacteria. phase76/phase77, 2026-07-13.

Intrinsic disorder (sequence + structure) highly disordered

carries a substantial disordered region (117/117 residues); disorder is a property, not a function

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).

Operon-context functional lead (hypothesis)

Co-transcribed within the operon Rv2766c-Rv2767c, pointing to fatty-acid synthesis.

Basis: co-transcription in operon Rv2766c-Rv2767c + purifying selection + coherent localisation. This is a contextual candidate association (guilt-by-co-transcription), not an established molecular function.

Roback 2007 check: NOT corroborated by the independently published operon map (Roback et al. 2007) — called group for this locus: Rv2767c, predicted co-transcription probability for the cited neighbour: 0.039936. Roback et al. 2007 (peer-reviewed operon map, PMID 17652327) does NOT corroborate the co-transcription claimed above (cited operon: Rv2766c-Rv2767c; Roback's called group for this locus: Rv2767c; predicted co-transcription probability for the cited neighbour: 0.039936). Verdict and function_revised are unchanged: the genomic neighbourhood and the named neighbour remain factual; only the co-transcription argument itself is now qualified by this independent source.

Two-source operon check: CONTREDIT 0/1 Whether the CITED NEIGHBOUR Rv2766c is co-transcribed, according to each independently published map — Roback 2007: different operons; REMap 2016 (RNA-seq coverage): pair not covered. Base rates over the adjacent gene pairs that could be an operon at all, i.e. the co-directional ones: Roback 39.2 %, REMap 67.7 % — an agreement is only informative above its own base rate, and that rate has to be read on the right denominator (over ALL adjacent pairs, opposite-strand ones included, the same rates read 26.3 % and 45.6 %, diluted by pairs that cannot be co-transcribed). Three-way operon check (CONTREDIT 0/1). The requalification argues co-transcription with Rv2766c (cited operon: Rv2766c-Rv2767c). Independent published maps: Roback et al. 2007 does NOT place it in the same operon (predicted probability 0.039936); REMap 2016 (RNA-seq coverage) does not cover this pair. This tests the claim actually made — whether the CITED NEIGHBOUR is co-transcribed — and not whether the three maps draw identical operon boundaries, which is a different question (strict group identity: Roback False, REMap None). Read each map against its own base rate, and against the RIGHT one: all twelve operon-based requalifications concern CO-DIRECTIONAL adjacent pairs, so the null is the rate over those pairs only — Roback calls co-transcription for 39.2 % of them (2429 pairs), REMap for 67.7 % (2230 pairs). Over all adjacent pairs, opposite-strand ones included, the same rates read 26.3 % and 45.6 %, but a divergent or convergent pair cannot form a transcription unit at all and neither map calls one (Roback 0.2 %, REMap 0.0 %), so that denominator dilutes the null instead of describing it. Against the conditioned null, REMap does not agree more often than chance across the twelve requalifications (9/10, one-sided binomial p = 0.116) and Roback does not either (5/12, p = 0.538). Correction of record (2026-10-09): until that date this sentence quoted the unconditioned null and reported REMap as significant (p = 0.00502); that significance does not survive the right denominator. So a lone REMap agreement is not a validation, and a lone Roback disagreement is weak evidence against the claim. Verdict, confidence and function_revised are unchanged; co-transcription remains an association, never a proof of shared function.

Genomic-neighbour overlap (structural caveat) co-directional · 1 % of gene

co-directional overlap: ordinary (e.g. shared stop/start codons in an operon), not the Rv2438A-type artefact P20.1, derived from GFF3 gene coordinates, 2026-08-03.

CRISPRi vulnerability

Vulnerability index -0.92 (95% CI -3.68 to 3.40). 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, supplementary Table S2 'mmc3.xlsx', bulk import via Europe PMC -- supersedes the per-gene pebble.rockefeller.edu scrape of phase46_crispri_vulnerability.py).

Caveat on this estimate. Bosch et al. flag this gene's vulnerability estimate as NOT certain, and here that call has a mechanical cause visible in the library itself: every guide targeting this gene is >=21 nt (str_span=0.018 on a 0-1 scale, near the genome floor), and guide repression strength saturates from 21 nt on -- so the library never sampled a partial knockdown for this gene, only the near-maximal repression plateau. The dose-response fit (and this VI) is therefore essentially unconstrained by data, not merely uncertain -- a limitation of the CRISPRi library design for the non-essential class (Bosch et al. 2021), not a defect in this specific measurement. n_guides=3 is descriptive only and does not predict this. Do not cite this VI as a standalone vulnerability claim.

Orthologues (reciprocal best hits across mycobacteria)

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)

Conservation & selection (intra-MTBC, 142 601 strains, snapshot of 2026-09-29)

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) MTBC-specific

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)

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.

Proteomics (mass spectrometry) not detected

Not detected in the mass-spectrometry datasets integrated by PaxDb. This is not evidence of absence, and this atlas can say which bias dominates, because it measured it on its own 482 undetected proteins. Size is the main factor: undetected proteins have a median length of 145 aa against 295 aa for detected ones, and 25.3 % of them are shorter than 100 aa against 6.0 %. Predicted localisation matters far less than usually assumed: detection rates are 89.3 % for globular, 84.9 % for transmembrane, 88.0 % for lipoproteins and 77.8 % for signal-peptide proteins — so a short protein is under-sampled whatever its predicted compartment, and hydrophobicity alone is a weak excuse. Condition-specific expression and few tryptic peptides (PE/PPE repeats) add to this.

Predicted localisation (DeepTMHMM + lipobox) no export signal, no TM helix

A verified absence of signals, which is not a compartment. No Sec/Tat signal peptide, no transmembrane helix and no lipobox were found on this sequence. The predictor reports topology and export signals; it does not measure where the protein ends up, so this page draws no cytoplasmic conclusion from it. In M. tuberculosis that reservation is not theoretical: the 12 Esx paralogues of this atlas — EsxA/ESAT-6 and EsxB/CFP-10 among them, the best-established secreted proteins of the species — carry this very call, because substrates of the type VII (ESX) secretion system leave no recognisable signal. « Secreted » and « no signal peptide » are true together here.

Transmembrane topology and signal peptide from DeepTMHMM (deep-learning reference predictor); lipoproteins from a (myco)bacterial lipobox motif. A sequence-based prediction of subcellular context.

Physico-chemical properties (computed, ProtParam)

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)

No Pfam-A domain above the gathering threshold (hmmscan --cut_ga scan completed).

3D structure (interactive — Mol*/pdbe-molstar)

No experimental structure is deposited for this gene: showing the AlphaFold DB predicted model (mean pLDDT 59.1, low), coloured by per-residue confidence (dark blue = very high, orange/red = low — treat low-confidence regions as unreliable, especially termini and loops). Drag to rotate, scroll to zoom.

Genomic context (neighbours & predicted operon) operon of 2

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).

Published operon evidence (two independent sources)

Two independent published operon maps, cited alongside the distance heuristic above: an association corroborating or contradicting the heuristic, never proof of shared function. REMap's RNA-seq coverage continuity is the most direct of the three signals; Roback's logistic regression and the intergenic-distance heuristic are statistical proxies.

Node colour = verdict, dashed = still uncharacterised; 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: PPE43 (PPE family protein PPE43), high confidence (score 891, all STRING channels except text-mining; the partner is chosen on its genomic-context evidence).

All 5 partner(s) at medium confidence are shown. None rests on an interaction measured in M. tuberculosis itself.

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 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.

Where the experimental evidence comes from, and why it matters here. STRING's experimental channel fuses interactions measured in M. tuberculosis with interactions measured in another organism and transferred to this pair by orthology. The two are not equivalent for this atlas, whose standing rule is that better studied elsewhere is not a function established in M. tuberculosis. Measured on the served network: of the 38 229 partner pairs shown across the atlas, 13 483 partner rows carry a non-zero experimental channel, and only 106 pairs rest on an interaction measured in M. tuberculosis itself — 0.3 % of the network. Those 106 are long-established complexes (ESX-1/ESAT-6, RNA polymerase with CarD and RbpA, the Pup–Mpa proteasome, gyrase, Emb, GarA with PknB and PknG, the Rel modules); no still-uncharacterised gene is among them. The reason is not a gap in this atlas but in the literature: there is almost no experimental interactome of this bacterium, IntAct holding 134 curated protein pairs for a ~4 000-gene proteome. A exp (transferred) badge is therefore a lead, never a measurement, and an absence of badge is not evidence that the pair does not interact.

Evidence

• Legacy H37Rv annotation: membrane protein
• MTBC0 PGAP product: hypothetical protein
• (initial automatic assignment: auto-curated by rules from PGAP + Pfam + Foldseek; superseded by hand review)

Ancestral MTBC0 protein sequence

>mtbc0_002945|Rv2767c|
MVGYEGARGRAGREMSESATAGARSSRIPFGIIRNHEAVRPRRSRHLNHARDTPQMVAVAQVWREVVQATAIAIAPPLPVVSWGLISLAFLSHTVRGRYRRSPPAESGHHSNRRQAK