Is TMC8 p.Arg466Trp (c.1396C>T) pathogenic?

TMC8 p.Arg466Trp (c.1396C>T) is classified Uncertain significance in TMC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-11). AlphaMissense: likely benign (0.1673); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with TMC8 p.Arg466Trp (c.1396C>T)?

TMC8 p.Arg466Trp (c.1396C>T) is associated with Inborn genetic diseases, epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Arg466Trp (c.1396C>T) in the general population?

TMC8 p.Arg466Trp (c.1396C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about TMC8 p.Arg466Trp (c.1396C>T)?

AlphaMissense predicts likely benign (score 0.1673) — an in-silico prediction, not a clinical call.

TMC8 p.Arg466Trp

c.1396C>T · rs149327841 · VCV1358494

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1673	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -9.45	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 0.6, phastCons 0.95
Regional constraint	o/e 0.97	unconstrained · MANE · 9,520 bp · p 0.44 · regional, not allelic
Overall
CADD	25.6	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 0.005% Admixed American · 3/60,018 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00347% 56/1,614,016 alleles · very rare exomes 48/1,461,740 · genomes 8/152,276 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,006
South Asian	0.00439%	22,770
European (non-Finnish)	0.00398%	25,107
Remaining individualsnot grpmax-eligible	0.0032%	31,255

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.Arg466Trp
Coding: c.1396C>T
MANE Select: NM_152468
dbSNP: rs149327841
Type: single nucleotide variant
Location: chr17:78138051 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 466: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epidermodysplasia verruciformis

Similar variants

TMC8 p.Arg466Gln Uncertain significance ★ ⚠ same residue
TMC8 p.Arg466= 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

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-arg466trp (accessed [today's date]).

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