Is COCH p.Pro51Ser (c.151C>T) pathogenic?

COCH p.Pro51Ser (c.151C>T) is classified Pathogenic in COCH (ClinVar, Expert panel, 9 submitters; last evaluated 2018-09-19). AlphaMissense: ambiguous (0.5178); Very rare (popmax 0.000254%, nfe); Associated with nonsyndromic genetic hearing loss.

What condition is associated with COCH p.Pro51Ser (c.151C>T)?

COCH p.Pro51Ser (c.151C>T) is associated with nonsyndromic genetic hearing loss, hearing loss disorder, autosomal dominant nonsyndromic hearing loss 9 (ClinVar).

How common is COCH p.Pro51Ser (c.151C>T) in the general population?

COCH p.Pro51Ser (c.151C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Rare non-syndromic genetic deafness inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COCH p.Pro51Ser (c.151C>T)?

AlphaMissense predicts ambiguous (score 0.5178) — an in-silico prediction, not a clinical call.

COCH p.Pro51Ser

c.151C>T · rs28938175 · VCV6611

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.5178 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

nonsyndromic genetic hearing loss

ClinGen expert panel — Hearing Loss VCEP

Pathogenic for nonsyndromic genetic deafness. Applied ACMG criteria (verbatim):

PM2 PP1_Strong PS4 PP3

Curation rationale (ClinGen, verbatim)

The c.151C>T (p.Pro51Ser) variant in COCH has been reported to segregate with late onset progressive hearing loss and vestibular dysfunction in > 25 family members (PP1_S; PMID: 9931344, 11332404). The variant meets PM2 and has been observed in at least 15 affected probands (PS4, PMID: 28733840, 16151338, 11332404). The allele frequency of the p.Pro51Ser variant is 0.001% (1/111716) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (PM2). Computational prediction tools and conservation analysis suggest that the p.Pro51Ser variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_S, PS4, PM2, PP3.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.5178	ambiguous
REVEL	0.873	moderately pathogenic-leaning
SaProt	LLR -11.15	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.0071 · regional, not allelic
Overall
CADD	26.1	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 0.000254% European (non-Finnish) · 3/1,180,038 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,888 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.Pro51Ser
Coding: c.151C>T
MANE Select: NM_004086
dbSNP: rs28938175
Type: single nucleotide variant
Location: chr14:30877640 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.93 · 1 PDB
Residue 51: a UniProt-annotated variant site (in dfna9; some families may manifest meniere disease-like symptoms; does not affect protein deposition to the extracellular matrix); the lccl domain

Full COCH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nonsyndromic genetic hearing loss — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hearing loss disorder autosomal dominant nonsyndromic hearing loss 9

For Rare non-syndromic genetic deafness (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

COCH p.Pro51Gln Likely pathogenic ★ ⚠ same residue
COCH p.Gly87Glu Likely 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.Arg180Ter Pathogenic/Likely pathogenic ★★ 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-pro51ser (accessed [today's date]).

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