Is COCH p.Pro516Ser (c.1546C>T) pathogenic?

COCH p.Pro516Ser (c.1546C>T) is classified Uncertain significance in COCH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-17). AlphaMissense: likely pathogenic (0.8514); Very rare (popmax 0.00134%, afr).

How common is COCH p.Pro516Ser (c.1546C>T) in the general population?

COCH p.Pro516Ser (c.1546C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about COCH p.Pro516Ser (c.1546C>T)?

AlphaMissense predicts likely pathogenic (score 0.8514) — an in-silico prediction, not a clinical call.

COCH p.Pro516Ser

c.1546C>T · rs917460112 · VCV1968154

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8514 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8514	likely pathogenic
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -10.56	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	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00134% African / African-American · 1/74,888 alleles

Overall 0.000657% 1/152,104 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.Pro516Ser
Coding: c.1546C>T
MANE Select: NM_004086
dbSNP: rs917460112
Type: single nucleotide variant
Location: chr14:30889684 (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

Similar variants

COCH p.Pro516Gln Likely pathogenic ★ same residue
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

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-pro516ser (accessed [today's date]).

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