Is COCH p.Arg384His (c.1151G>A) pathogenic?

COCH p.Arg384His (c.1151G>A) is classified Uncertain significance in COCH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-11). AlphaMissense: likely benign (0.0883); Ultra-rare (popmax 0.0472%, sas).

How common is COCH p.Arg384His (c.1151G>A) in the general population?

COCH p.Arg384His (c.1151G>A) is ultra-rare (popmax 0.0472%, sas) (gnomAD).

What do computational predictors say about COCH p.Arg384His (c.1151G>A)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

COCH p.Arg384His

c.1151G>A · rs545418366 · VCV1202378

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0472%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
REVEL	0.337	indeterminate
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -0.44, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.0071 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0472% South Asian · 43/91,082 alleles

Filtering AF 0.036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0321%

Overall 0.0057% 92/1,614,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0472%	2,118
African / African-American	0.0147%	6,820
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	0.00297%	33,715
East Asian	0.00223%	44,884

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.Arg384His
Coding: c.1151G>A
MANE Select: NM_004086
dbSNP: rs545418366
Type: single nucleotide variant
Location: chr14:30885986 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.93 · 1 PDB
Residue 384: 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.Arg384Cys Conflicting classifications of pathogenicity ★ ⚠ 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-arg384his (accessed [today's date]).

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