Is TMC8 p.Arg255Gln (c.764G>A) pathogenic?

TMC8 p.Arg255Gln (c.764G>A) is classified Uncertain significance in TMC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-17). AlphaMissense: likely benign (0.0722); Ultra-rare (popmax 0.048%, afr); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Arg255Gln (c.764G>A)?

TMC8 p.Arg255Gln (c.764G>A) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Arg255Gln (c.764G>A) in the general population?

TMC8 p.Arg255Gln (c.764G>A) is ultra-rare (popmax 0.048%, afr) (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 TMC8 p.Arg255Gln (c.764G>A)?

AlphaMissense predicts likely benign (score 0.0722) — an in-silico prediction, not a clinical call.

TMC8 p.Arg255Gln

c.764G>A · rs150810138 · VCV845524

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0722 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
AlphaMissense	0.0722	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -5.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.91	acceptor gain · deltas
Pangolin	Δ0.36	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.031	GERP -2.5
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	21.9	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 0.048% African / African-American · 36/74,944 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.00508% 82/1,613,546 alleles · ultra-rare exomes 67/1,461,330 · genomes 15/152,216 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.048%	2,082
Admixed American	0.00833%	12,000
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.00322%	31,054

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: TMC8
Protein: p.Arg255Gln
Coding: c.764G>A
MANE Select: NM_152468
dbSNP: rs150810138
Type: single nucleotide variant
Location: chr17:78133948 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77

Full TMC8 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

TMC8 c.1824-1G>C Pathogenic/Likely pathogenic ★★ same condition
TMC8 c.449-1G>T Likely pathogenic ★★ same condition
TMC8 p.Arg190Ter Pathogenic ★★ same condition
TMC8 p.Ala188Val Uncertain significance ★★ ⚠ same condition
TMC8 p.Ala290Thr Uncertain significance ★★ ⚠ same condition
TMC8 p.Ala313Val Uncertain significance ★★ ⚠ same condition
TMC8 p.Ala316Thr Uncertain significance ★★ ⚠ same condition
TMC8 p.Ala345Thr 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/tmc8-p-arg255gln (accessed [today's date]).

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