Is TMC1 p.Ala690= (c.2070G>A) pathogenic?

TMC1 p.Ala690= (c.2070G>A) is classified Conflicting classifications of pathogenicity in TMC1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.085%, amr); Associated with autosomal recessive nonsyndromic hearing loss 7.

What condition is associated with TMC1 p.Ala690= (c.2070G>A)?

TMC1 p.Ala690= (c.2070G>A) is associated with autosomal recessive nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 36 (ClinVar).

How common is TMC1 p.Ala690= (c.2070G>A) in the general population?

TMC1 p.Ala690= (c.2070G>A) is ultra-rare (popmax 0.085%, amr) (gnomAD).

TMC1 p.Ala690=

c.2070G>A · rs145757452 · VCV165441

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.085%, amr)

Conditions

autosomal recessive nonsyndromic hearing loss 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.7	GERP -4.1
Overall
CADD	4.549	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.085% Admixed American · 51/59,992 alleles

Filtering AF 0.0664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0598%

Overall 0.0177% 286/1,613,950 alleles · ultra-rare exomes 261/1,461,806 · genomes 25/152,144 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.085%	1,176
Middle Eastern	0.0657%	1,521
Remaining individualsnot grpmax-eligible	0.048%	2,083
European (non-Finnish)	0.0158%	6,310
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,401
African / African-American	0.012%	8,322
South Asian	0.0011%	91,088

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.Ala690=
Coding: c.2070G>A
MANE Select: NM_138691
dbSNP: rs145757452
Type: single nucleotide variant
Location: chr9:72826935 (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

autosomal recessive nonsyndromic hearing loss 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 36

Similar variants

TMC1 p.Ala690Thr Uncertain significance ★★ ⚠ 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-ala690 (accessed [today's date]).

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