Is TMC6 p.Arg231Cys (c.691C>T) pathogenic?

TMC6 p.Arg231Cys (c.691C>T) is classified Uncertain significance in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-11). AlphaMissense: likely benign (0.1248); Very rare (popmax 0.00565%, sas); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC6 p.Arg231Cys (c.691C>T)?

TMC6 p.Arg231Cys (c.691C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Arg231Cys (c.691C>T) in the general population?

TMC6 p.Arg231Cys (c.691C>T) is very rare (popmax 0.00565%, 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.Arg231Cys (c.691C>T)?

AlphaMissense predicts likely benign (score 0.1248) — an in-silico prediction, not a clinical call.

TMC6 p.Arg231Cys

c.691C>T · rs566431890 · VCV1057437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1248 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00565%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
AlphaMissense	0.1248	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -11.18	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.88 · regional, not allelic
Overall
CADD	28.5	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 0.00565% South Asian · 5/88,538 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0014%

Overall 0.00132% 21/1,591,598 alleles · very rare exomes 17/1,439,260 · genomes 4/152,338 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00565%	17,708
East Asian	0.00229%	43,716
Admixed American	0.00178%	56,086
Remaining individualsnot grpmax-eligible	0.00162%	61,652
African / African-American	0.00134%	74,616
European (non-Finnish)	0.00103%	97,472

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.Arg231Cys
Coding: c.691C>T
MANE Select: NM_001127198
dbSNP: rs566431890
Type: single nucleotide variant
Location: chr17:78124724 (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.Arg231His Uncertain significance ★ ⚠ same residue
TMC6 p.Arg231Leu 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

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-arg231cys (accessed [today's date]).

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