# NM_004606.5(TAF1):c.4276A>G (p.Met1426Val)

https://sugi.bio/variant/taf1-p-met1426val

## Summary

**TAF1 p.Met1426Val (c.4276A>G)** is classified **Likely pathogenic** in TAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-26). AlphaMissense: ambiguous (0.3959); Absent from gnomAD v4.1.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2148488085 · 1 submitter · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TAF1 gene that is considered likely disease-causing, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TAF1](https://sugi.bio/atlas/gene/TAF1/) |
| Protein change (HGVS p.) | p.Met1426Val |
| Coding change (HGVS c.) | c.4276A>G |
| MANE Select transcript | [NM_004606](https://www.ncbi.nlm.nih.gov/nuccore/NM_004606) |
| dbSNP | [rs2148488085](https://www.ncbi.nlm.nih.gov/snp/rs2148488085/) |
| Variant type | single nucleotide variant |
| Location | chrX:71408043-71408043 (GRCh38) |
| ClinVar | [VCV1098389](https://www.ncbi.nlm.nih.gov/clinvar/variation/1098389/) |

**All HGVS expressions:** `NC_000023.10:g.70627893A>G`, `NC_000023.11:g.71408043A>G`, `NG_012771.2:g.46780A>G`, `NM_001286074.2:c.4276A>G`, `NM_004606.5:c.4276A>G`, `NM_138923.4:c.4213A>G`, `NR_104387.2:n.4294A>G`, `NR_104388.2:n.4294A>G`, `NR_104389.2:n.4294A>G`, `NR_104390.2:n.4294A>G`, `NR_104391.2:n.4294A>G`, `NR_104392.2:n.4294A>G`, `NR_104393.2:n.4294A>G`, `NR_104394.2:n.4294A>G`, `NR_104395.2:n.4294A>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense, REVEL and SaProt make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3959) — no call either way
- REVEL 0.436 (indeterminate)
- Conservation: phyloP 11.052, GERP 1.67, phastCons 1 — highly conserved
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **M1425V** vs ClinVar **M1426V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 24.6**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.39** across the covering region of the MANE Select transcript (71,406,668–71,424,029), spanning 17,361 bp. Chi-square p 4.2e-15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 62.62, 27% of residues very-high.

**65 experimental structure(s)** (PDB): [1EQF](https://www.rcsb.org/structure/1EQF), [3AAD](https://www.rcsb.org/structure/3AAD), [3UV4](https://www.rcsb.org/structure/3UV4), [3UV5](https://www.rcsb.org/structure/3UV5), [4RGW](https://www.rcsb.org/structure/4RGW), [4YYM](https://www.rcsb.org/structure/4YYM).

## What this gene does {#gene-function}

*Describes the biological roles of TAF1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TAF1's established molecular role includes RNA polymerase II core promoter sequence-specific DNA binding. p.Met1426Val falls in the interaction with asf1a and asf1b region. In Reactome, TAF1 is annotated in disease pathway(s) including **HIV Transcription Initiation**, **RNA Polymerase II HIV Promoter Escape**.

**Disease mechanism (Reactome):** TAF1 loss or alteration is curated in [HIV Transcription Initiation](https://reactome.org/content/detail/R-HSA-167161), [RNA Polymerase II HIV Promoter Escape](https://reactome.org/content/detail/R-HSA-167162), [Transcription of the HIV genome](https://reactome.org/content/detail/R-HSA-167172).

### Pathways affected {#pathways}

TAF1 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [HIV Transcription Initiation](https://reactome.org/content/detail/R-HSA-167161) | electronic |
| ⚕ [RNA Polymerase II HIV Promoter Escape](https://reactome.org/content/detail/R-HSA-167162) | electronic |
| ⚕ [Transcription of the HIV genome](https://reactome.org/content/detail/R-HSA-167172) | electronic |
| [RNA Polymerase II Pre-transcription Events](https://reactome.org/content/detail/R-HSA-674695) | curated |
| [RNA Polymerase II Promoter Escape](https://reactome.org/content/detail/R-HSA-73776) | curated |
| [RNA Polymerase II Transcription Initiation](https://reactome.org/content/detail/R-HSA-75953) | curated |
| [RNA Polymerase II Transcription Initiation And Promoter Clearance](https://reactome.org/content/detail/R-HSA-76042) | curated |
| [RNA Polymerase II Transcription Pre-Initiation And Promoter Opening](https://reactome.org/content/detail/R-HSA-73779) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA polymerase II core promoter sequence-specific DNA binding, RNA polymerase II general transcription initiation factor binding, RNA polymerase I general transcription initiation factor activity, p53 binding, histone acetyltransferase activity, protein kinase activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, protein polyubiquitination, transcription initiation at RNA polymerase I promoter, transcription by RNA polymerase II, transcription initiation at RNA polymerase II promoter, ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-04-26.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-04-26 |

**Reported phenotype names (ClinVar):** See cases.

## Similar variants {#similar}

Related TAF1 variant pages (same residue, condition, or type): [TAF1 p.Arg1062Cys](/variant/taf1-p-arg1062cys), [TAF1 p.Arg1234Gln](/variant/taf1-p-arg1234gln), [TAF1 p.Arg1432His](/variant/taf1-p-arg1432his), [TAF1 p.Arg870Cys](/variant/taf1-p-arg870cys), [TAF1 p.Asn1497His](/variant/taf1-p-asn1497his), [TAF1 p.Ile1317Thr](/variant/taf1-p-ile1317thr), [TAF1 p.Phe403Val](/variant/taf1-p-phe403val), [TAF1 c.1774-3T>C](/variant/taf1-c-1774-minus-3t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1098389). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*