Is TMC6 p.Ala451= (c.1353C>T) pathogenic?

TMC6 p.Ala451= (c.1353C>T) is classified Likely benign in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-26). Very rare (popmax 0.00167%, amr); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC6 p.Ala451= (c.1353C>T)?

TMC6 p.Ala451= (c.1353C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Ala451= (c.1353C>T) in the general population?

TMC6 p.Ala451= (c.1353C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC6 p.Ala451=

c.1353C>T · rs770521551 · VCV2158707

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.2	GERP -2.3
Overall
CADD	0.874	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,996 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,611,542 alleles · very rare exomes 7/1,459,420 · genomes 0/152,122 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,356
European (non-Finnish)	0.000424%	235,942

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: TMC6
Protein: p.Ala451=
Coding: c.1353C>T
MANE Select: NM_001127198
dbSNP: rs770521551
Type: single nucleotide variant
Location: chr17:78121586 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.56

Full TMC6 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

TMC6 p.Arg94Ter Pathogenic ★★ same condition
TMC6 c.1383+4C>T Uncertain significance ★★ same condition
TMC6 p.Ala124Pro Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala212Val Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala233Thr Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala380Thr Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala432Val Uncertain significance ★★ ⚠ same condition
TMC6 p.Ala495Thr 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/tmc6-p-ala451 (accessed [today's date]).

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