Is TMC8 p.Cys398Arg (c.1192T>C) pathogenic?

TMC8 p.Cys398Arg (c.1192T>C) is classified Uncertain significance in TMC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.7695); Absent from gnomAD v4.1; Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Cys398Arg (c.1192T>C)?

TMC8 p.Cys398Arg (c.1192T>C) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Cys398Arg (c.1192T>C) in the general population?

TMC8 p.Cys398Arg (c.1192T>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.Cys398Arg (c.1192T>C)?

AlphaMissense predicts likely pathogenic (score 0.7695) — an in-silico prediction, not a clinical call.

TMC8 p.Cys398Arg

c.1192T>C · rs2510806093 · VCV1994634

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7695 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
AlphaMissense	0.7695	likely pathogenic · top 8% in TMC8
REVEL	0.27	benign-leaning
SaProt	LLR -10.51	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	25.7	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

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.Cys398Arg
Coding: c.1192T>C
MANE Select: NM_152468
dbSNP: rs2510806093
Type: single nucleotide variant
Location: chr17:78137299 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 398: the 'tmc domain' region; a UniProt-annotated variant site (in ev2)

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-cys398arg (accessed [today's date]).

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