Is TMC1 p.Leu730Phe (c.2188C>T) pathogenic?

TMC1 p.Leu730Phe (c.2188C>T) is classified Uncertain significance in TMC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). AlphaMissense: likely pathogenic (0.753); Very rare (popmax 6.2e-05%); Associated with Inborn genetic diseases.

What condition is associated with TMC1 p.Leu730Phe (c.2188C>T)?

TMC1 p.Leu730Phe (c.2188C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TMC1 p.Leu730Phe (c.2188C>T) in the general population?

TMC1 p.Leu730Phe (c.2188C>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about TMC1 p.Leu730Phe (c.2188C>T)?

AlphaMissense predicts likely pathogenic (score 0.753) — an in-silico prediction, not a clinical call.

TMC1 p.Leu730Phe

c.2188C>T · VCV3326506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.753	likely pathogenic
REVEL	0.739	pathogenic-leaning
SaProt	LLR -11.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 187 kb · p 0.0013 · regional, not allelic
Overall
CADD	24.0	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 6.2e-05%

Overall 6.2e-05% 1/1,613,336 alleles · very rare exomes 1/1,461,276 · genomes 0/152,060 · 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: TMC1
Protein: p.Leu730Phe
Coding: c.2188C>T
MANE Select: NM_138691
Type: single nucleotide variant
Location: chr9:72830509 (GRCh38)
Gene constraint: LOEUF 0.914 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 1 PDB

Full TMC1 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

Similar variants

TMC1 p.Trp588Ter Pathogenic ★★ same condition
TMC1 p.Ala150Thr Uncertain significance ★★ ⚠ same condition
TMC1 p.Ala394Ser Uncertain significance ★★ ⚠ same condition
TMC1 p.Ala690Thr Uncertain significance ★★ ⚠ same condition
TMC1 p.Arg141Gln Uncertain significance ★★ ⚠ same condition
TMC1 p.Arg264Gln Uncertain significance ★★ same condition
TMC1 p.Arg264Pro Uncertain significance ★★ ⚠ same condition
TMC1 p.Arg512Gln 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/tmc1-p-leu730phe (accessed [today's date]).

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