Is COCH p.Leu9Val (c.25C>G) pathogenic?

COCH p.Leu9Val (c.25C>G) is classified Conflicting classifications of pathogenicity in COCH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-07-05). AlphaMissense: likely benign (0.0663); Very rare (popmax 0.005%, amr).

How common is COCH p.Leu9Val (c.25C>G) in the general population?

COCH p.Leu9Val (c.25C>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about COCH p.Leu9Val (c.25C>G)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

COCH p.Leu9Val

c.25C>G · rs760397052 · VCV514369

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -7.76	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 0.075	GERP -2.7, phastCons 0.002
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.0071 · regional, not allelic
Overall
CADD	12.2	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 0.005% Admixed American · 3/60,010 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00229% 37/1,613,384 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
Finnishnot grpmax-eligible	0.00472%	21,197
Remaining individualsnot grpmax-eligible	0.0032%	31,236
European (non-Finnish)	0.00237%	42,138
African / African-American	0.00133%	74,920

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.Leu9Val
Coding: c.25C>G
MANE Select: NM_004086
dbSNP: rs760397052
Type: single nucleotide variant
Location: chr14:30874963 (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

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-leu9val (accessed [today's date]).

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