Is TMC1 p.Arg264Pro (c.791G>C) pathogenic?

TMC1 p.Arg264Pro (c.791G>C) is classified Uncertain significance in TMC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-03). AlphaMissense: likely pathogenic (0.8866); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TMC1 p.Arg264Pro (c.791G>C)?

TMC1 p.Arg264Pro (c.791G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TMC1 p.Arg264Pro (c.791G>C) in the general population?

TMC1 p.Arg264Pro (c.791G>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about TMC1 p.Arg264Pro (c.791G>C)?

AlphaMissense predicts likely pathogenic (score 0.8866) — an in-silico prediction, not a clinical call.

TMC1 p.Arg264Pro

c.791G>C · rs147147941 · VCV47878

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8866	likely pathogenic
REVEL	0.212	benign-leaning
SaProt	LLR -7.34	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 187 kb · p 0.0013 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,816 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,696 alleles · very rare exomes 4/1,461,630 · genomes 1/152,066 · 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.Arg264Pro
Coding: c.791G>C
MANE Select: NM_138691
dbSNP: rs147147941
Type: single nucleotide variant
Location: chr9:72772462 (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.Arg264Gln Uncertain significance ★★ same residue
TMC1 p.Arg264Ter Pathogenic ★★ same residue
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.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-arg264pro (accessed [today's date]).

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