Is TMC8 p.Arg301Pro (c.902G>C) pathogenic?

TMC8 p.Arg301Pro (c.902G>C) is classified Uncertain significance in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-01). AlphaMissense: likely benign (0.332); Ultra-rare (popmax 0.0802%, eas); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Arg301Pro (c.902G>C)?

TMC8 p.Arg301Pro (c.902G>C) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Arg301Pro (c.902G>C) in the general population?

TMC8 p.Arg301Pro (c.902G>C) is ultra-rare (popmax 0.0802%, eas) (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.Arg301Pro (c.902G>C)?

AlphaMissense predicts likely benign (score 0.332) — an in-silico prediction, not a clinical call.

TMC8 p.Arg301Pro

c.902G>C · rs553175400 · VCV1978939

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.332 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0802%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
AlphaMissense	0.332	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	24.2	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 0.0802% East Asian · 36/44,874 alleles

Filtering AF 0.0595% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0524%

Overall 0.00235% 38/1,614,032 alleles · ultra-rare exomes 31/1,461,744 · genomes 7/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0802%	1,247
Admixed American	0.00167%	60,016
European (non-Finnish)	8.47e-05%	1,180,032

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.Arg301Pro
Coding: c.902G>C
MANE Select: NM_152468
dbSNP: rs553175400
Type: single nucleotide variant
Location: chr17:78134479 (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.Arg301Trp Uncertain significance ★★ ⚠ 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-arg301pro (accessed [today's date]).

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