Is TMC6 p.Val593Ile (c.1777G>A) pathogenic?

TMC6 p.Val593Ile (c.1777G>A) is classified Uncertain significance in TMC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-02). AlphaMissense: likely benign (0.1629); Ultra-rare (popmax 0.0183%, amr); Associated with Inborn genetic diseases.

What condition is associated with TMC6 p.Val593Ile (c.1777G>A)?

TMC6 p.Val593Ile (c.1777G>A) is associated with Inborn genetic diseases, epidermodysplasia verruciformis (ClinVar).

How common is TMC6 p.Val593Ile (c.1777G>A) in the general population?

TMC6 p.Val593Ile (c.1777G>A) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about TMC6 p.Val593Ile (c.1777G>A)?

AlphaMissense predicts likely benign (score 0.1629) — an in-silico prediction, not a clinical call.

TMC6 p.Val593Ile

c.1777G>A · rs1422742102 · VCV2277290

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1629	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -8.66	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.88 · regional, not allelic
Overall
CADD	23.3	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 0.0183% Admixed American · 11/60,026 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000743% 12/1,614,100 alleles · ultra-rare exomes 12/1,461,776 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,457
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Val593Ile
Coding: c.1777G>A
MANE Select: NM_001127198
dbSNP: rs1422742102
Type: single nucleotide variant
Location: chr17:78119331 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epidermodysplasia verruciformis

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-val593ile (accessed [today's date]).

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