Is TMC1 p.Pro511His (c.1532C>A) pathogenic?

TMC1 p.Pro511His (c.1532C>A) is classified Conflicting classifications of pathogenicity in TMC1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2020-08-01). AlphaMissense: likely pathogenic (0.9102); Very rare (popmax 8.47e-05%, nfe); Associated with TMC1-related disorder.

What condition is associated with TMC1 p.Pro511His (c.1532C>A)?

TMC1 p.Pro511His (c.1532C>A) is associated with TMC1-related disorder, autosomal recessive nonsyndromic hearing loss 7 (ClinVar).

How common is TMC1 p.Pro511His (c.1532C>A) in the general population?

TMC1 p.Pro511His (c.1532C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TMC1 p.Pro511His (c.1532C>A)?

AlphaMissense predicts likely pathogenic (score 0.9102) — an in-silico prediction, not a clinical call.

TMC1 p.Pro511His

c.1532C>A · rs727503483 · VCV165436

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9102 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

TMC1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9102	likely pathogenic
REVEL	0.382	indeterminate
SaProt	LLR -13.20	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 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 187 kb · p 0.0013 · regional, not allelic
Overall
CADD	27.3	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 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 0.000137% 2/1,461,854 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)grpmax	8.47e-05%	1,180,012

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro511His
Coding: c.1532C>A
MANE Select: NM_138691
dbSNP: rs727503483
Type: single nucleotide variant
Location: chr9:72792318 (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

TMC1-related disorder

Also linked: autosomal recessive nonsyndromic hearing loss 7

Similar variants

TMC1 p.Pro511Leu Pathogenic same residue
TMC1 c.1405-2A>T Likely pathogenic ★★ same condition
TMC1 c.1763+3A>G Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.236+1G>A Pathogenic ★★ same condition
TMC1 c.64+2T>A Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.741+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMC1 c.884+1G>A Pathogenic ★★ same condition
TMC1 p.Arg264Ter Pathogenic ★★ 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-pro511his (accessed [today's date]).

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