Is COCH p.Leu114Phe (c.340C>T) pathogenic?

COCH p.Leu114Phe (c.340C>T) is classified Uncertain significance in COCH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-29). AlphaMissense: likely benign (0.2254); Ultra-rare (popmax 0.0165%, mid).

How common is COCH p.Leu114Phe (c.340C>T) in the general population?

COCH p.Leu114Phe (c.340C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about COCH p.Leu114Phe (c.340C>T)?

AlphaMissense predicts likely benign (score 0.2254) — an in-silico prediction, not a clinical call.

COCH p.Leu114Phe

c.340C>T · rs924049830 · VCV1483684

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2254 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2254	likely benign
REVEL	0.629	indeterminate
SaProt	LLR -6.11	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 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.0071 · regional, not allelic
Overall
CADD	25.4	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 0.0165% Middle Eastern · 1/6,074 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000434% 7/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,074
South Asian	0.00329%	30,359
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00133%	74,922
European (non-Finnish)	8.47e-05%	1,180,020

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.Leu114Phe
Coding: c.340C>T
MANE Select: NM_004086
dbSNP: rs924049830
Type: single nucleotide variant
Location: chr14:30878911 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.93 · 1 PDB
Residue 114: a UniProt-annotated variant site (in dfnb110); the lccl domain

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

Similar variants

COCH p.Leu114Val Likely pathogenic ★ ⚠ same residue
COCH p.Leu114His Uncertain significance ★ ⚠ 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

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-leu114phe (accessed [today's date]).

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