Is TMC1 p.Val651Phe (c.1951G>T) pathogenic?

TMC1 p.Val651Phe (c.1951G>T) is classified Uncertain significance in TMC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-02). AlphaMissense: likely pathogenic (0.7569); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TMC1 p.Val651Phe (c.1951G>T)?

TMC1 p.Val651Phe (c.1951G>T) is associated with Inborn genetic diseases (ClinVar).

How common is TMC1 p.Val651Phe (c.1951G>T) in the general population?

TMC1 p.Val651Phe (c.1951G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMC1 p.Val651Phe (c.1951G>T)?

AlphaMissense predicts likely pathogenic (score 0.7569) — an in-silico prediction, not a clinical call.

TMC1 p.Val651Phe

c.1951G>T · rs2489985217 · VCV2275146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7569 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7569	likely pathogenic
REVEL	0.461	indeterminate
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 187 kb · p 0.0013 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMC1
Protein: p.Val651Phe
Coding: c.1951G>T
MANE Select: NM_138691
dbSNP: rs2489985217
Type: single nucleotide variant
Location: chr9:72821029 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 1 PDB

Full TMC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMC1 p.Trp588Ter Pathogenic ★★ same condition
TMC1 p.Ala150Thr Uncertain significance ★★ ⚠ same condition
TMC1 p.Ala394Ser Uncertain significance ★★ ⚠ same condition
TMC1 p.Ala690Thr Uncertain significance ★★ ⚠ same condition
TMC1 p.Arg141Gln Uncertain significance ★★ ⚠ same condition
TMC1 p.Arg264Gln Uncertain significance ★★ same condition
TMC1 p.Arg264Pro Uncertain significance ★★ ⚠ same condition
TMC1 p.Arg512Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tmc1-p-val651phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown