Is TMC8 p.Trp91Arg (c.271T>C) pathogenic?

TMC8 p.Trp91Arg (c.271T>C) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-19). AlphaMissense: likely pathogenic (0.931); Absent from gnomAD v4.1; Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Trp91Arg (c.271T>C)?

TMC8 p.Trp91Arg (c.271T>C) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Trp91Arg (c.271T>C) in the general population?

TMC8 p.Trp91Arg (c.271T>C) is absent from gnomAD v4.1 (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.Trp91Arg (c.271T>C)?

AlphaMissense predicts likely pathogenic (score 0.931) — an in-silico prediction, not a clinical call.

TMC8 p.Trp91Arg

c.271T>C · rs2145578233 · VCV1352753

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.931 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epidermodysplasia verruciformis

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.931	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	LLR -12.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMC8
Protein: p.Trp91Arg
Coding: c.271T>C
MANE Select: NM_152468
dbSNP: rs2145578233
Type: single nucleotide variant
Location: chr17:78132003 (GRCh38)

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

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-trp91arg (accessed [today's date]).

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