Is ESPN p.Arg774Gln (c.2321G>A) pathogenic?

ESPN p.Arg774Gln (c.2321G>A) is classified Pathogenic in ESPN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2006-02-01). AlphaMissense: likely benign (0.0903); Very rare (popmax 0.00243%, eas); Associated with autosomal dominant nonsyndromic hearing loss 91.

What condition is associated with ESPN p.Arg774Gln (c.2321G>A)?

ESPN p.Arg774Gln (c.2321G>A) is associated with autosomal dominant nonsyndromic hearing loss 91 (ClinVar).

How common is ESPN p.Arg774Gln (c.2321G>A) in the general population?

ESPN p.Arg774Gln (c.2321G>A) is very rare (popmax 0.00243%, eas) (gnomAD).

What do computational predictors say about ESPN p.Arg774Gln (c.2321G>A)?

AlphaMissense predicts likely benign (score 0.0903) — an in-silico prediction, not a clinical call.

ESPN p.Arg774Gln

c.2321G>A · rs121908136 · VCV4422

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00243%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant nonsyndromic hearing loss 91

Computational evidence

Protein change
AlphaMissense	0.0903	likely benign ⚠ discordant with ClinVar
REVEL	0.462	indeterminate
SaProt	LLR -9.25	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 7.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	27.0	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

Grpmax group 0.00243% East Asian · 1/41,104 alleles

Filtering AF 0.000787% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000624%

Overall 0.0011% 17/1,543,026 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00243%	41,104
Admixed American	0.00194%	51,444
European (non-Finnish)	0.00131%	76,309

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: ESPN
Protein: p.Arg774Gln
Coding: c.2321G>A
MANE Select: NM_031475
dbSNP: rs121908136
Type: single nucleotide variant
Location: chr1:6452092 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 774: the 'disordered' region; a UniProt-annotated variant site (in dfnb36; uncertain significance)

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

Disease context

autosomal dominant nonsyndromic hearing loss 91 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESPN p.Asp744Asn Uncertain significance ★★ ⚠ same condition
ESPN p.Ser719Arg Likely pathogenic ★ ⚠ same condition
ESPN p.Lys848del Likely pathogenic ★ same condition
ESPN c.1464+1G>A Likely pathogenic ★★ same type
ESPN p.Ala139Thr Uncertain significance ★★ ⚠ same type
ESPN p.Ala23Thr Uncertain significance ★★ ⚠ same type
ESPN p.Ala484Thr Uncertain significance ★★ ⚠ same type
ESPN p.Ala591Val Uncertain significance ★★ ⚠ 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/espn-p-arg774gln (accessed [today's date]).

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