Is COCH p.Ala231Val (c.692C>T) pathogenic?

COCH p.Ala231Val (c.692C>T) is classified Uncertain significance in COCH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: ambiguous (0.5099); Ultra-rare (popmax 0.0153%, nfe).

How common is COCH p.Ala231Val (c.692C>T) in the general population?

COCH p.Ala231Val (c.692C>T) is ultra-rare (popmax 0.0153%, nfe) (gnomAD).

What do computational predictors say about COCH p.Ala231Val (c.692C>T)?

AlphaMissense predicts ambiguous (score 0.5099) — an in-silico prediction, not a clinical call.

COCH p.Ala231Val

c.692C>T · VCV4538054

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5099 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0153%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5099	ambiguous
REVEL	0.806	moderately pathogenic-leaning
SaProt	LLR -11.16	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.0071 · regional, not allelic
Overall
CADD	28.7	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 0.0153% European (non-Finnish) · 180/1,179,720 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0127%

Overall 0.0116% 187/1,613,478 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0153%	6,554
Remaining individualsnot grpmax-eligible	0.0048%	20,820
African / African-American	0.00401%	24,952
Admixed American	0.00167%	59,992

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.Ala231Val
Coding: c.692C>T
MANE Select: NM_004086
Type: single nucleotide variant
Location: chr14:30884615 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.93 · 1 PDB
Residue 231: a UniProt-annotated variant site (in dfnb110); the vwfa 1 domain

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

Similar variants

COCH p.Gly87Glu Likely pathogenic ★★★ same type
COCH p.Pro51Ser Pathogenic ★★★ ⚠ same type
COCH p.Ala119Thr Uncertain significance ★★★ ⚠ same type
COCH c.629+5C>T Benign ★★★ same type
COCH p.Asp281Asn Benign ★★★ same type
COCH p.Pro143= Benign ★★★ same type
COCH c.1477+1G>C Likely pathogenic ★★ same type
COCH p.Arg180Ter Pathogenic/Likely pathogenic ★★ same type

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-ala231val (accessed [today's date]).

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