Is COCH p.Pro516Gln (c.1547C>A) pathogenic?

COCH p.Pro516Gln (c.1547C>A) is classified Likely pathogenic in COCH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). AlphaMissense: likely pathogenic (0.8691); Very rare (popmax 0.000339%, nfe); Associated with autosomal dominant nonsyndromic hearing loss 9.

What condition is associated with COCH p.Pro516Gln (c.1547C>A)?

COCH p.Pro516Gln (c.1547C>A) is associated with autosomal dominant nonsyndromic hearing loss 9 (ClinVar).

How common is COCH p.Pro516Gln (c.1547C>A) in the general population?

COCH p.Pro516Gln (c.1547C>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about COCH p.Pro516Gln (c.1547C>A)?

AlphaMissense predicts likely pathogenic (score 0.8691) — an in-silico prediction, not a clinical call.

COCH p.Pro516Gln

c.1547C>A · VCV3601051

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 9

Computational evidence

Protein change
AlphaMissense	0.8691	likely pathogenic ✓ concordant with ClinVar
REVEL	0.867	moderately pathogenic-leaning
SaProt	LLR -11.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.0071 · regional, not allelic
Overall
CADD	28.6	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 0.000339% European (non-Finnish) · 4/1,179,830 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,644 alleles · very rare

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.Pro516Gln
Coding: c.1547C>A
MANE Select: NM_004086
Type: single nucleotide variant
Location: chr14:30889685 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.93 · 1 PDB
Residue 516: a UniProt-annotated variant site (in dfnb110); the vwfa 2 domain

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.Pro516Ser Uncertain significance ★ ⚠ same residue
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

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-pro516gln (accessed [today's date]).

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