Is COCH p.Ala3Pro (c.7G>C) pathogenic?

COCH p.Ala3Pro (c.7G>C) is classified Uncertain significance in COCH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-02). AlphaMissense: likely benign (0.1285); Very rare (popmax 0.00178%, nfe); Associated with autosomal dominant nonsyndromic hearing loss 9.

What condition is associated with COCH p.Ala3Pro (c.7G>C)?

COCH p.Ala3Pro (c.7G>C) is associated with autosomal dominant nonsyndromic hearing loss 9 (ClinVar).

How common is COCH p.Ala3Pro (c.7G>C) in the general population?

COCH p.Ala3Pro (c.7G>C) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about COCH p.Ala3Pro (c.7G>C)?

AlphaMissense predicts likely benign (score 0.1285) — an in-silico prediction, not a clinical call.

COCH p.Ala3Pro

c.7G>C · VCV3376698

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1285 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 9

Computational evidence

Protein change
AlphaMissense	0.1285	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -5.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.59, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.0071 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00178% European (non-Finnish) · 21/1,179,822 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00136% 22/1,613,316 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00178%	56,182
African / African-American	0.00134%	74,888

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: COCH
Protein: p.Ala3Pro
Coding: c.7G>C
MANE Select: NM_004086
Type: single nucleotide variant
Location: chr14:30874945 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.93 · 1 PDB

Full COCH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant nonsyndromic hearing loss 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COCH p.Gly87Glu Likely pathogenic ★★★ same condition
COCH p.Pro51Ser Pathogenic ★★★ same condition
COCH p.Ala119Thr Uncertain significance ★★★ ⚠ same condition
COCH c.629+5C>T Benign ★★★ same condition
COCH p.Asp281Asn Benign ★★★ same condition
COCH p.Pro143= Benign ★★★ same condition
COCH p.Arg98Ter Likely pathogenic ★★ same condition
COCH p.Cys542Phe 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/coch-p-ala3pro (accessed [today's date]).

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