Is TMC6 p.Ala794Pro (c.2380G>C) pathogenic?

TMC6 p.Ala794Pro (c.2380G>C) is classified Uncertain significance in TMC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-09). AlphaMissense: likely benign (0.0668); Rare (popmax 0.149%, afr); Associated with Inborn genetic diseases.

What condition is associated with TMC6 p.Ala794Pro (c.2380G>C)?

TMC6 p.Ala794Pro (c.2380G>C) is associated with Inborn genetic diseases, epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Ala794Pro (c.2380G>C) in the general population?

TMC6 p.Ala794Pro (c.2380G>C) is rare (popmax 0.149%, afr) (gnomAD).

What do computational predictors say about TMC6 p.Ala794Pro (c.2380G>C)?

AlphaMissense predicts likely benign (score 0.0668) — an in-silico prediction, not a clinical call.

TMC6 p.Ala794Pro

c.2380G>C · rs112660101 · VCV849550

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0668 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0668	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.7	GERP -2.3
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.88 · regional, not allelic
Overall
CADD	0.009	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.149% African / African-American · 110/74,016 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.00822% 128/1,557,834 alleles · rare exomes 73/1,405,512 · genomes 55/152,322 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.149%	673
Middle Eastern	0.0503%	1,987
Remaining individualsnot grpmax-eligible	0.0199%	5,024
Admixed American	0.00578%	17,309

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TMC6
Protein: p.Ala794Pro
Coding: c.2380G>C
MANE Select: NM_001127198
dbSNP: rs112660101
Type: single nucleotide variant
Location: chr17:78113186 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.56
Residue 794: the 'disordered' region

Full TMC6 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

Also linked: epidermodysplasia verruciformis

Similar variants

TMC6 p.Ala794Thr Uncertain significance ★ ⚠ same residue
TMC6 p.Arg94Ter Pathogenic ★★ same condition
TMC6 c.1383+4C>T Uncertain significance ★★ same condition
TMC6 p.Ala124Pro Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala212Val Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala233Thr Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala380Thr Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala432Val 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/tmc6-p-ala794pro (accessed [today's date]).

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