Is TMC8 p.Arg459Trp (c.1375C>T) pathogenic?

TMC8 p.Arg459Trp (c.1375C>T) is classified Conflicting classifications of pathogenicity in TMC8 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-25). AlphaMissense: likely benign (0.0807); Very rare (popmax 0.00439%, sas); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Arg459Trp (c.1375C>T)?

TMC8 p.Arg459Trp (c.1375C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Arg459Trp (c.1375C>T) in the general population?

TMC8 p.Arg459Trp (c.1375C>T) is very rare (popmax 0.00439%, sas) (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.Arg459Trp (c.1375C>T)?

AlphaMissense predicts likely benign (score 0.0807) — an in-silico prediction, not a clinical call.

TMC8 p.Arg459Trp

c.1375C>T · rs764442700 · VCV948363

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
AlphaMissense	0.0807	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.64	GERP -3.4
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	16.83	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

Grpmax group 0.00439% South Asian · 4/91,084 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.0026% 42/1,613,874 alleles · very rare exomes 39/1,461,720 · genomes 3/152,154 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,771
European (non-Finnish)	0.00305%	32,778
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,912

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.Arg459Trp
Coding: c.1375C>T
MANE Select: NM_152468
dbSNP: rs764442700
Type: single nucleotide variant
Location: chr17:78138030 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 459: 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 p.Arg459Gln Uncertain significance ★★ ⚠ same residue
TMC8 p.Arg459Gly 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

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-arg459trp (accessed [today's date]).

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