# NM_004086.3(COCH):c.151C>T (p.Pro51Ser)

https://sugi.bio/variant/coch-p-pro51ser

## Summary

**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.

**At a glance:** Pathogenic · review: Expert panel · rsID rs28938175 · 9 submitters · 3 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the COCH gene that is considered disease-causing, submitted by 9 submitters, and is linked to nonsyndromic genetic hearing loss.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | COCH is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Rare non-syndromic genetic deafness** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Prelingual sensorineural hearing impairment — Frequent (79-30%)
- Progressive sensorineural hearing impairment — Frequent (79-30%)
- Delayed speech and language development — Frequent (79-30%)
- Abnormal speech discrimination — Frequent (79-30%)
- Postlingual sensorineural hearing impairment — Frequent (79-30%)
- Profound sensorineural hearing impairment — Frequent (79-30%)
- Conductive hearing impairment — Occasional (29-5%)
- High-frequency hearing impairment — Occasional (29-5%)

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COCH](https://sugi.bio/atlas/gene/COCH/) |
| Protein change (HGVS p.) | p.Pro51Ser |
| Coding change (HGVS c.) | c.151C>T |
| MANE Select transcript | [NM_004086](https://www.ncbi.nlm.nih.gov/nuccore/NM_004086) |
| dbSNP | [rs28938175](https://www.ncbi.nlm.nih.gov/snp/rs28938175/) |
| Variant type | single nucleotide variant |
| Location | chr14:30877640-30877640 (GRCh38) |
| ClinVar | [VCV6611](https://www.ncbi.nlm.nih.gov/clinvar/variation/6611/) |

**All HGVS expressions:** `NC_000014.8:g.31346846C>T`, `NC_000014.9:g.30877640C>T`, `NG_008211.2:g.8106C>T`, `NM_001135058.2:c.151C>T`, `NM_001347720.2:c.346C>T`, `NM_004086.3:c.151C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5178) — no call either way
- REVEL 0.873 (moderately pathogenic-leaning)
- SaProt LLR -11.151 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 7.67, GERP 1.64, phastCons 1 — highly conserved
- CADD: **PHRED 26.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.90** across the covering region of the MANE Select transcript (30,874,939–30,889,788), spanning 14,849 bp. Chi-square p 0.0071. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,180,038 in the highest group · 3/1,461,888 alleles overall — very rare (popmax 0.000254%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**COCH** population constraint: LOEUF 0.896, pLI 5.7486e-09, missense-Z 1.3663. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **nonsyndromic genetic hearing loss** — Definitive (AD)

## Protein context {#protein}

Residue **51** lies in 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.

AlphaFold model confidence (whole protein): pLDDT 85.93, 61% of residues very-high.

**1 experimental structure(s)** (PDB): [1JBI](https://www.rcsb.org/structure/1JBI).

## What this gene does {#gene-function}

*Describes the biological roles of COCH (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** COCH's established molecular role includes collagen binding. p.Pro51Ser falls in the lccl domain.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** collagen binding.

**Biological process:** regulation of cell shape.

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2018-09-19.

**Submitter consensus:** conflicting (8 Pathogenic, 1 Likely pathogenic).

**Submission history:** 9 submissions (2009–2025); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Hearing Loss VCEP (nonsyndromic genetic deafness). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2`, `PP1_Strong`, `PS4`, `PP3`.
*Considered but not met:* `PM6`, `PVS1`, `PS1`, `PS2`, `PS3`, `PM1`, `PP2`, `PP4`, `BS2`, `PM3`, `BS1`, `BS4`, `BS3`, `BP5`, `BP7`, `PM5`, `BP4`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Autosomal dominant inheritance.

> **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.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50007 · approved 2018-09-19 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/d4782d4a-27b7-4626-acc7-f8758d33384d).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2009-02-01 |
| ClinGen Hearing Loss Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2018-09-19 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-09 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2011-11-14 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-07 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2018-08-01 |
| Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-04-12 |

## Associated conditions {#conditions}

[nonsyndromic genetic hearing loss](https://sugi.bio/atlas/disease/nonsyndromic-genetic-hearing-loss/), [hearing loss disorder](https://sugi.bio/atlas/disease/hearing-loss-disorder/), [autosomal dominant nonsyndromic hearing loss 9](https://sugi.bio/atlas/disease/autosomal-dominant-nonsyndromic-hearing-loss-9/).

**Reported phenotype names (ClinVar):** Nonsyndromic genetic hearing loss, Autosomal dominant nonsyndromic hearing loss 9, Rare genetic deafness, not provided, Hearing impairment, COCH-related disorder, COCH-related condition, Nonsyndromic genetic deafness, Nonsyndromic hearing loss and deafness, Non-syndromic genetic deafness.

## Same-residue context {#hotspot}

Residue **51** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [COCH p.Pro51Gln](/variant/coch-p-pro51gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related COCH variant pages (same residue, condition, or type): [COCH p.Pro51Gln](/variant/coch-p-pro51gln), [COCH p.Gly87Glu](/variant/coch-p-gly87glu), [COCH p.Ala119Thr](/variant/coch-p-ala119thr), [COCH c.629+5C>T](/variant/coch-c-629-plus-5c-t), [COCH p.Asp281Asn](/variant/coch-p-asp281asn), [COCH p.Pro143=](/variant/coch-p-pro143), [COCH p.Arg180Ter](/variant/coch-p-arg180ter), [COCH p.Arg98Ter](/variant/coch-p-arg98ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 6611). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*