Is TMC6 p.Pro137Ser (c.409C>T) pathogenic?

TMC6 p.Pro137Ser (c.409C>T) is classified Uncertain significance in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: likely benign (0.0748); Very rare (popmax 0.00368%, amr); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC6 p.Pro137Ser (c.409C>T)?

TMC6 p.Pro137Ser (c.409C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Pro137Ser (c.409C>T) in the general population?

TMC6 p.Pro137Ser (c.409C>T) is very rare (popmax 0.00368%, amr) (gnomAD).

How is Inherited epidermodysplasia verruciformis inherited?

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

What do computational predictors say about TMC6 p.Pro137Ser (c.409C>T)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

TMC6 p.Pro137Ser

c.409C>T · rs758391457 · VCV964841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00368%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -5.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.55	GERP -2, phastCons 0.001
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.88 · regional, not allelic
Overall
CADD	3.956	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 0.00368% Admixed American · 2/54,280 alleles

Filtering AF 0.000611% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000373%

Overall 0.000892% 14/1,568,856 alleles · very rare exomes 11/1,416,540 · genomes 3/152,316 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00368%	27,140
Remaining individualsnot grpmax-eligible	0.00165%	60,766
European (non-Finnish)	0.00095%	105,211

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.Pro137Ser
Coding: c.409C>T
MANE Select: NM_001127198
dbSNP: rs758391457
Type: single nucleotide variant
Location: chr17:78125747 (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-pro137ser (accessed [today's date]).

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