Is TMC8 p.Val575= (c.1725C>T) pathogenic?

TMC8 p.Val575= (c.1725C>T) is classified Likely benign in TMC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). Rare (popmax 0.172%, nfe); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC8 p.Val575= (c.1725C>T)?

TMC8 p.Val575= (c.1725C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC8 p.Val575= (c.1725C>T) in the general population?

TMC8 p.Val575= (c.1725C>T) is rare (popmax 0.172%, nfe) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TMC8 p.Val575=

c.1725C>T · rs141186150 · VCV456025

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.172%, nfe)

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.094	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.86	GERP 0.49, phastCons 0.002
Overall
CADD	3.366	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.172% European (non-Finnish) · 2,031/1,180,036 alleles

Filtering AF 0.166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.163%

Overall 0.149% 2,410/1,613,978 alleles · rare exomes 2,231/1,461,584 · genomes 179/152,394 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.172%	581
Middle Eastern	0.148%	674
Finnishnot grpmax-eligible	0.138%	725
South Asian	0.133%	753
Remaining individualsnot grpmax-eligible	0.12%	833
Ashkenazi Jewishnot grpmax-eligible	0.115%	871
Admixed American	0.05%	2,001
African / African-American	0.0213%	4,693
East Asian	0.0134%	7,482

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.Val575=
Coding: c.1725C>T
MANE Select: NM_152468
dbSNP: rs141186150
Type: single nucleotide variant
Location: chr17:78138634 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.77
Residue 575: 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-val575 (accessed [today's date]).

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