Is TMC6 p.Pro677Ser (c.2029C>T) pathogenic?

TMC6 p.Pro677Ser (c.2029C>T) is classified Uncertain significance in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-11). AlphaMissense: likely pathogenic (0.6638); Very rare (popmax 0.00232%, sas); Associated with epidermodysplasia verruciformis.

What condition is associated with TMC6 p.Pro677Ser (c.2029C>T)?

TMC6 p.Pro677Ser (c.2029C>T) is associated with epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Pro677Ser (c.2029C>T) in the general population?

TMC6 p.Pro677Ser (c.2029C>T) is very rare (popmax 0.00232%, sas) (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.Pro677Ser (c.2029C>T)?

AlphaMissense predicts likely pathogenic (score 0.6638) — an in-silico prediction, not a clinical call.

TMC6 p.Pro677Ser

c.2029C>T · rs1197288239 · VCV2900432

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00232%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

epidermodysplasia verruciformis

Computational evidence

Protein change
AlphaMissense	0.6638	likely pathogenic
REVEL	0.619	indeterminate
SaProt	LLR -11.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.88 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00232% South Asian · 2/86,272 alleles

Filtering AF 0.000385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000144%

Overall 0.000141% 2/1,417,658 alleles · very rare

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.Pro677Ser
Coding: c.2029C>T
MANE Select: NM_001127198
dbSNP: rs1197288239
Type: single nucleotide variant
Location: chr17:78117637 (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-pro677ser (accessed [today's date]).

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