Is TMC8 p.Ala240Val (c.719C>T) pathogenic?

TMC8 p.Ala240Val (c.719C>T) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-29). AlphaMissense: likely benign (0.0745); Very rare (popmax 0.00333%, amr); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Ala240Val (c.719C>T)?

TMC8 p.Ala240Val (c.719C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Ala240Val (c.719C>T) in the general population?

TMC8 p.Ala240Val (c.719C>T) is very rare (popmax 0.00333%, amr) (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.Ala240Val (c.719C>T)?

AlphaMissense predicts likely benign (score 0.0745) — an in-silico prediction, not a clinical call.

TMC8 p.Ala240Val

c.719C>T · rs757640069 · VCV663103

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0745 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
AlphaMissense	0.0745	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -6.56	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 1.2	GERP -2.5, phastCons 0.32
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	10.68	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 0.00333% Admixed American · 2/60,020 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00093% 15/1,613,526 alleles · very rare exomes 15/1,461,138 · genomes 0/152,388 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,010
East Asian	0.00223%	44,886
South Asian	0.0022%	45,546
European (non-Finnish)	0.000847%	118,004

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.Ala240Val
Coding: c.719C>T
MANE Select: NM_152468
dbSNP: rs757640069
Type: single nucleotide variant
Location: chr17:78133903 (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 p.Ala240= Likely benign ★ same residue
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

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-ala240val (accessed [today's date]).

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