Is TMC6 p.Val433Ala (c.1298T>C) pathogenic?

TMC6 p.Val433Ala (c.1298T>C) is classified Conflicting classifications of pathogenicity in TMC6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-21). AlphaMissense: likely benign (0.0747); Ultra-rare (popmax 0.0102%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TMC6 p.Val433Ala (c.1298T>C)?

TMC6 p.Val433Ala (c.1298T>C) is associated with Inborn genetic diseases, epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Val433Ala (c.1298T>C) in the general population?

TMC6 p.Val433Ala (c.1298T>C) is ultra-rare (popmax 0.0102%, nfe) (gnomAD).

What do computational predictors say about TMC6 p.Val433Ala (c.1298T>C)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

TMC6 p.Val433Ala

c.1298T>C · rs954564790 · VCV645821

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -7.27	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 1.5	GERP -2.3, phastCons 0.006
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.88 · regional, not allelic
Overall
CADD	8.616	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

Grpmax group 0.0102% European (non-Finnish) · 120/1,177,938 alleles

Filtering AF 0.00869% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00766% 123/1,605,850 alleles · ultra-rare exomes 118/1,453,738 · genomes 5/152,112 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0102%	9,816
Remaining individualsnot grpmax-eligible	0.00483%	20,703

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.Val433Ala
Coding: c.1298T>C
MANE Select: NM_001127198
dbSNP: rs954564790
Type: single nucleotide variant
Location: chr17:78121641 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.56

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.Val433Leu 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-val433ala (accessed [today's date]).

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