Is TMC6 p.Ser709= (c.2127C>T) pathogenic?

TMC6 p.Ser709= (c.2127C>T) is classified Likely benign in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-19). Ultra-rare (popmax 0.0361%, eas); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC6 p.Ser709= (c.2127C>T)?

TMC6 p.Ser709= (c.2127C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Ser709= (c.2127C>T) in the general population?

TMC6 p.Ser709= (c.2127C>T) is ultra-rare (popmax 0.0361%, eas) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC6 p.Ser709=

c.2127C>T · rs770819421 · VCV1952668

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0361%, eas)

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 0.9	GERP -2.5, phastCons 1
Overall
CADD	8.541	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0361% East Asian · 16/44,368 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.000999% 16/1,601,542 alleles · ultra-rare exomes 9/1,449,342 · genomes 7/152,200 · joint denominator

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.Ser709=
Coding: c.2127C>T
MANE Select: NM_001127198
dbSNP: rs770819421
Type: single nucleotide variant
Location: chr17:78117539 (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.Ser709Phe Uncertain significance ★ ⚠ same residue
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

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-ser709 (accessed [today's date]).

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