Is TMC1 p.Pro566Ser (c.1696C>T) pathogenic?

TMC1 p.Pro566Ser (c.1696C>T) is classified Uncertain significance in TMC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-13). AlphaMissense: likely pathogenic (0.9898); Very rare (popmax 8.48e-05%, nfe); Associated with TMC1-related disorder.

What condition is associated with TMC1 p.Pro566Ser (c.1696C>T)?

TMC1 p.Pro566Ser (c.1696C>T) is associated with TMC1-related disorder (ClinVar).

How common is TMC1 p.Pro566Ser (c.1696C>T) in the general population?

TMC1 p.Pro566Ser (c.1696C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TMC1 p.Pro566Ser (c.1696C>T)?

AlphaMissense predicts likely pathogenic (score 0.9898) — an in-silico prediction, not a clinical call.

TMC1 p.Pro566Ser

c.1696C>T · rs2118284014 · VCV2632373

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9898 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

TMC1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9898	likely pathogenic · top 9% in TMC1
REVEL	0.373	indeterminate
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 187 kb · p 0.0013 · regional, not allelic
Overall
CADD	29.7	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 8.48e-05% European (non-Finnish) · 1/1,179,324 alleles

Overall 6.84e-05% 1/1,460,982 alleles · very rare

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.Pro566Ser
Coding: c.1696C>T
MANE Select: NM_138691
dbSNP: rs2118284014
Type: single nucleotide variant
Location: chr9:72816143 (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

Similar variants

TMC1 p.Pro566Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TMC1 c.236+1G>A Pathogenic ★★ same condition
TMC1 p.Arg34Ter Pathogenic ★★ same condition
TMC1 p.Arg604Ter Pathogenic ★★ same condition
TMC1 p.Asp572Asn Pathogenic/Likely pathogenic ★★ ⚠ same condition
TMC1 p.Asp572His Pathogenic/Likely pathogenic ★★ ⚠ same condition
TMC1 p.Asp684His Pathogenic/Likely pathogenic ★★ same condition
TMC1 p.Trp111Ter Pathogenic/Likely 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-pro566ser (accessed [today's date]).

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