Is COCH p.Ile166Val (c.496A>G) pathogenic?

COCH p.Ile166Val (c.496A>G) is classified Uncertain significance in COCH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-22). AlphaMissense: likely benign (0.1125); Ultra-rare (popmax 0.0367%, amr).

How common is COCH p.Ile166Val (c.496A>G) in the general population?

COCH p.Ile166Val (c.496A>G) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

What do computational predictors say about COCH p.Ile166Val (c.496A>G)?

AlphaMissense predicts likely benign (score 0.1125) — an in-silico prediction, not a clinical call.

COCH p.Ile166Val

c.496A>G · rs771810191 · VCV1901437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1125 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1125	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -7.18	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 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.0071 · regional, not allelic
Overall
CADD	22.1	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 0.0367% Admixed American · 22/60,006 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00229% 37/1,614,044 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,728
Remaining individualsnot grpmax-eligible	0.0064%	15,622
South Asian	0.0011%	91,082
European (non-Finnish)	0.000847%	118,005

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.Ile166Val
Coding: c.496A>G
MANE Select: NM_004086
dbSNP: rs771810191
Type: single nucleotide variant
Location: chr14:30880601 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.93 · 1 PDB
Residue 166: 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-ile166val (accessed [today's date]).

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