Rv2256a Still unknown · low auto-curated
H37Rv Rv2256a · MTBC0 - ·
64 aa ·
2528980–2529174 H37Rv
(-) ·
RefSeq YP_009030037.1
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Annotation: from legacy to revised
| Legacy (H37Rv / Mycobrowser) | hypothetical protein |
|---|---|
| MTBC0 PGAP re-annotation | — |
| Revised (this work) | Conserved hypothetical protein; no recognised domain. Function unknown. |
Auto-curated: this verdict and function were generated by rules from PGAP + Pfam + Foldseek and have not been hand-reviewed.
Annotated on the H37Rv protein: this gene has no 1:1 ancestral MTBC0 anchor (PE/PPE, paralogue, IS element, or otherwise unanchored CDS).
In the literature (TB corpus sweep) named only in full text
No TB publication mentions this locus tag in its title or abstract (sweep of a ~330k-abstract PubMed TB corpus). A full-text search does however find 1 paper(s) naming this gene in their body text — see the full-text field below. The gene remains dark on function, but it is not unmentioned, and this page no longer claims that it is.
Rv2256a
in Europe PMC full text (2026-09-08).
- Whole genome sequencing, analyses of drug resistance-conferring mutations, and correlation (2019, open access)
A full-text hit means the gene is NAMED in the body of a paper — very often in a genome-wide supplementary table — not that it is characterised. This field exists to retract an absence claim, never to assert a function. Read the hits before concluding anything. Coverage limit (P52.4, measured 2026-09-30): this search only sees articles whose full text Europe PMC holds, about 8-13 % of the TB literature published before 2005, 21 % for 2005-2009, 40 % for 2010-2014 and 66 % since 2020, so the absence of a hit says little about older mentions. A hit whose full text is not open access is counted in n_unverifiable, not listed: the API cannot read it, so it is neither a proof of mention nor a proof of absence.
Second-source check (P43.6): tbmonitor finds 0 paper(s) naming this locus tag, the PubMed sweep 0 — no mention in either source. Neither source is complete: across the 210 fiches whose source verdict is dark, 3 are seen only by tbmonitor and 4 only by PubMed, which is why a 'no mention in the literature' statement is never made on a single source here. (The site's own counter reports 209: Rv2438A carries a curated function and is recalled to family_assigned at ingest by the verdict/function coherence guard, so it leaves the dark tally without leaving this cross-check.) A count above zero says the gene has been NAMED in a paper, not that its molecular function is known: Rv2660c carries 38 papers as the latency antigen of the multistage vaccine H56 (Ag85B + ESAT-6 + Rv2660c, Aagaard et al., Nat Med 2011, PMID 21258338) and is still dark on function. Counts are shown side by side and never merged.
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).
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) dark by construction (IDR-orphan)
| Predicted disorder | 100% of residues (metapredict) |
|---|---|
| Disordered regions | 1 IDR(s), longest 64 aa [0-64] |
both sequence (metapredict) and structure (low AlphaFold pLDDT) indicate little stable globular structure: this gene is dark BY CONSTRUCTION — there is no confident fold for structure/homology search to match, so its obscurity is expected, not a pipeline failure
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).
Conditional expression context (iModulons)
Member of 1 independently-modulated gene set(s):
Rv1828/SigH (Rv1828 or sigH).
iModulon membership (independently-modulated gene sets from a 647-sample RNA-seq compendium): the conditional co-expression context. Co-expression is a regulatory context, NOT a molecular function. Source: iModulonDB / modulome_mtb (Yoo 2022).
Conservation & selection (intra-MTBC, 142 601 strains, snapshot of 2026-09-29)
| pN/pS | 0.376 · quasi-invariant (2 sites), pN/pS underpowered |
|---|---|
| Polymorphic sites (≥ 0.1% of strains) | 1 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) Mycobacterium
| Genus-wide presence (~53 non-MTBC Mycobacterium) |
present in 5/53 (9%) · mean identity 46.8%
· 0/4 closest MTBAP relatives SENSITIVITY DOWNGRADE: a divergent homolog is detectable at relaxed thresholds (weak hit 48%/69%cov in M_liflandii — likely present but divergent); NOT a robust MTBC-specific innovation — present but divergent. The strict tblastn absence was a coverage/identity-threshold artefact. |
|---|---|
| Phylostratum (deepest detected homolog) |
MTBC-specific → Mycobacterium → Mycobacteriaceae → Corynebacteriales → Actinomycetia → Bacteria short ORF (64 aa) a shallow stratum may reflect homology-detection failure, not true youth present across the genus Mycobacterium (NTM) but not detected in any non-Mycobacterium genome — a Mycobacterium-genus 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.
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
| Prediction | no signal peptide, no TM helix (DeepTMHMM class GLOB) |
|---|---|
| DeepTMHMM class | GLOB |
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)
| Length | 64 aa |
|---|---|
| Molecular weight | 7.0 kDa |
| Theoretical pI | 11.22 |
| GRAVY | -0.328 (hydrophilic) |
| Aliphatic index | 89.8 |
| Aromaticity | 0.031 |
| Instability index | 54.5 (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)
No Pfam-A domain above the gathering threshold (hmmscan --cut_ga scan completed).
HHpred profile-profile (no confident hit): No confident hit (best 29%, E=190) — pure noise. Remains dark.
top hits all hits <29% probability, E>=130 (YuaX, DUF5805, GntR).
Remote homology search on the deep UniRef30 profile (MPI Toolkit), run for the residual dark set.
Genomic context (neighbours & predicted operon) operon of 2
| Upstream (5' on genome) | Rv2254c (- strand, 4 bp gap) |
|---|---|
| Downstream (3' on genome) | Rv2256c (- strand, 166 bp gap) |
| Predicted operon |
Rv2254c · Rv2256a
|
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)
| Roback 2007 (logistic regression: distance + expression correlation, 474 microarrays) | no multi-gene operon predicted (singleton) — disagrees with the distance heuristic above |
|---|
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.
Functional interaction network (STRING v12)
This gene is absent from the STRING v12 proteome for M. tuberculosis H37Rv, so no interaction evidence could be queried for it at all — which is a statement about STRING's gene set, not about the protein.
Evidence
- Annotation from H37Rv (no MTBC0 1:1 anchor; H37Rv protein used): hypothetical protein
- (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 YP_009030037.1)
- Domains: Pfam-A via hmmscan --cut_ga — none above threshold
- Sequence-level signal: ESM Atlas (EvolutionaryScale × BioHub) — exploratory
- Intra-MTBC selection: pN/pS and disruption from SPDI variants of 142 601 MTBC strains (this work, local collection vs H37Rv NC_000962.3)
- Genomic context / operon: H37Rv annotation; operon predicted by co-directional intergenic distance (Salgado et al. 2000, doi:10.1073/pnas.030539397)
- Physico-chemical properties: ExPASy ProtParam method via Biopython (Gasteiger et al. 2005), computed from the MTBC0 sequence
- Predicted localisation: DeepTMHMM (Hallgren et al. 2022, doi:10.1101/2022.04.08.487609) for transmembrane topology and signal peptide
- Primary literature: none located yet; annotation rests on the domain/homology sources above.
Ancestral MTBC0 protein sequence
>H37Rv|Rv2256a| MDGIVDRGVRARPCQKVVAVLRRSKSHIDKRLDAATGNAFLGKQVLSAAGVVEYRPPRRSPLST
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