Is COCH p.Ile450Val (c.1348A>G) pathogenic?

COCH p.Ile450Val (c.1348A>G) is classified Conflicting classifications of pathogenicity in COCH (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.1533); Rare (popmax 0.331%, mid); Associated with autosomal dominant nonsyndromic hearing loss 9.

What condition is associated with COCH p.Ile450Val (c.1348A>G)?

COCH p.Ile450Val (c.1348A>G) is associated with autosomal dominant nonsyndromic hearing loss 9 (ClinVar).

How common is COCH p.Ile450Val (c.1348A>G) in the general population?

COCH p.Ile450Val (c.1348A>G) is rare (popmax 0.331%, mid) (gnomAD).

What do computational predictors say about COCH p.Ile450Val (c.1348A>G)?

AlphaMissense predicts likely benign (score 0.1533) — an in-silico prediction, not a clinical call.

COCH p.Ile450Val

c.1348A>G · rs139503327 · VCV228523

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1533 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.331%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant nonsyndromic hearing loss 9

Computational evidence

Protein change
AlphaMissense	0.1533	likely benign
REVEL	0.422	indeterminate
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.0071 · regional, not allelic
Overall
CADD	23.1	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 0.331% Middle Eastern · 20/6,046 alleles

Filtering AF 0.219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.183%

Overall 0.0748% 1,204/1,610,614 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.331%	302
Finnishnot grpmax-eligible	0.109%	914
Remaining individualsnot grpmax-eligible	0.0915%	1,093
Admixed American	0.0819%	1,221
European (non-Finnish)	0.0799%	1,251
South Asian	0.0572%	1,749
African / African-American	0.0147%	6,810
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,369

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.Ile450Val
Coding: c.1348A>G
dbSNP: rs139503327
Type: single nucleotide variant
Location: chr14:30886183 (GRCh38)

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

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-ile450val (accessed [today's date]).

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