Is ESPN p.Glu658Lys (c.1972G>A) pathogenic?

ESPN p.Glu658Lys (c.1972G>A) is classified Likely pathogenic in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: likely pathogenic (0.9223); Absent from gnomAD v4.1; Associated with autosomal recessive nonsyndromic hearing loss 36.

What condition is associated with ESPN p.Glu658Lys (c.1972G>A)?

ESPN p.Glu658Lys (c.1972G>A) is associated with autosomal recessive nonsyndromic hearing loss 36 (ClinVar).

How common is ESPN p.Glu658Lys (c.1972G>A) in the general population?

ESPN p.Glu658Lys (c.1972G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ESPN p.Glu658Lys (c.1972G>A)?

AlphaMissense predicts likely pathogenic (score 0.9223) — an in-silico prediction, not a clinical call.

ESPN p.Glu658Lys

c.1972G>A · rs1643945526 · VCV2445625

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9223 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive nonsyndromic hearing loss 36

Computational evidence

Protein change
AlphaMissense	0.9223	likely pathogenic ✓ concordant with ClinVar · top 9% in ESPN
REVEL	0.309	indeterminate
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.36, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ESPN
Protein: p.Glu658Lys
Coding: c.1972G>A
MANE Select: NM_031475
dbSNP: rs1643945526
Type: single nucleotide variant
Location: chr1:6451659 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 658: the wh2 domain; the 'disordered' region

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

Disease context

autosomal recessive nonsyndromic hearing loss 36 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESPN c.1464+1G>A Likely pathogenic ★★ same condition
ESPN p.Ala624Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Arg755Cys Uncertain significance ★★ ⚠ same condition
ESPN p.Asp744Asn Uncertain significance ★★ ⚠ same condition
ESPN p.Gly747Ser Uncertain significance ★★ ⚠ same condition
ESPN p.Lys476Gln Uncertain significance ★★ ⚠ same condition
ESPN p.Ser312Leu Uncertain significance ★★ ⚠ same condition
ESPN p.Ser362Leu Uncertain significance ★★ ⚠ 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/espn-p-glu658lys (accessed [today's date]).

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