Is TMC6 p.Ser123= (c.369C>T) pathogenic?

TMC6 p.Ser123= (c.369C>T) is classified Likely benign in TMC6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Rare (popmax 0.283%, mid); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC6 p.Ser123= (c.369C>T)?

TMC6 p.Ser123= (c.369C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Ser123= (c.369C>T) in the general population?

TMC6 p.Ser123= (c.369C>T) is rare (popmax 0.283%, mid) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

TMC6 p.Ser123=

c.369C>T · rs142758270 · VCV526258

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.283%, mid)

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 -14	GERP -2
Overall
CADD	1.392	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.283% Middle Eastern · 17/6,008 alleles

Filtering AF 0.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.148%

Overall 0.116% 1,811/1,562,150 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.283%	353
European (non-Finnish)	0.132%	755
South Asian	0.127%	786
Remaining individualsnot grpmax-eligible	0.106%	945
Admixed American	0.0944%	1,059
East Asian	0.0409%	2,448
African / African-American	0.0327%	3,062
Finnishnot grpmax-eligible	0.00504%	19,850

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.Ser123=
Coding: c.369C>T
MANE Select: NM_001127198
dbSNP: rs142758270
Type: single nucleotide variant
Location: chr17:78125787 (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-ser123 (accessed [today's date]).

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