Is TMC6 p.Ile460= (c.1380C>T) pathogenic?

TMC6 p.Ile460= (c.1380C>T) is classified Likely benign in TMC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-21). Very rare (popmax 0.000339%, nfe).

How common is TMC6 p.Ile460= (c.1380C>T) in the general population?

TMC6 p.Ile460= (c.1380C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

TMC6 p.Ile460=

c.1380C>T · VCV4937171

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

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 -0.61	GERP -1.4
Overall
CADD	0.903	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,726 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,611,274 alleles · very rare exomes 4/1,459,110 · genomes 0/152,164 · 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.Ile460=
Coding: c.1380C>T
MANE Select: NM_001127198
Type: single nucleotide variant
Location: chr17:78121559 (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

Similar variants

TMC6 p.Ile460Thr Uncertain significance ★ ⚠ same residue
TMC6 p.Arg94Ter Pathogenic ★★ same type
TMC6 c.1383+4C>T Uncertain significance ★★ same type
TMC6 p.Ala124Pro Uncertain significance ★★ ⚠ same type
TMC6 p.Ala212Val Uncertain significance ★★ ⚠ same type
TMC6 p.Ala233Thr Uncertain significance ★★ ⚠ same type
TMC6 p.Ala380Thr Uncertain significance ★★ ⚠ same type
TMC6 p.Ala432Val Uncertain significance ★★ ⚠ same type

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-ile460 (accessed [today's date]).

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