Is TMC6 p.Ala413Pro (c.1237G>C) pathogenic?

TMC6 p.Ala413Pro (c.1237G>C) is classified Conflicting classifications of pathogenicity in TMC6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-25). AlphaMissense: ambiguous (0.5397); Rare (popmax 0.274%, sas); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC6 p.Ala413Pro (c.1237G>C)?

TMC6 p.Ala413Pro (c.1237G>C) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Ala413Pro (c.1237G>C) in the general population?

TMC6 p.Ala413Pro (c.1237G>C) is rare (popmax 0.274%, sas) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TMC6 p.Ala413Pro (c.1237G>C)?

AlphaMissense predicts ambiguous (score 0.5397) — an in-silico prediction, not a clinical call.

TMC6 p.Ala413Pro

c.1237G>C · rs555453763 · VCV788265

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5397 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.274%, sas)

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
AlphaMissense	0.5397	ambiguous
REVEL	0.302	indeterminate
SaProt	LLR -8.62	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.057, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.88 · regional, not allelic
Overall
CADD	24.2	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 0.274% South Asian · 245/89,298 alleles

Filtering AF 0.246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.235%

Overall 0.0482% 765/1,586,432 alleles · rare exomes 684/1,434,096 · genomes 81/152,336 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.274%	364
Middle Eastern	0.232%	431
Finnishnot grpmax-eligible	0.182%	549
Remaining individualsnot grpmax-eligible	0.0439%	2,277
European (non-Finnish)	0.0309%	3,238
Ashkenazi Jewishnot grpmax-eligible	0.0206%	4,846
Admixed American	0.0107%	9,369
African / African-American	0.00536%	18,654

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.Ala413Pro
Coding: c.1237G>C
MANE Select: NM_001127198
dbSNP: rs555453763
Type: single nucleotide variant
Location: chr17:78121702 (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

epidermodysplasia verruciformis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Inherited epidermodysplasia verruciformis (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

TMC6 p.Ala413= Likely benign ★ 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-ala413pro (accessed [today's date]).

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