Is ESPN p.Asp304Tyr (c.910G>T) pathogenic?

ESPN p.Asp304Tyr (c.910G>T) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-17). AlphaMissense: ambiguous (0.4176); Ultra-rare (popmax 0.0183%, mid); Associated with sensorineural hearing loss disorder.

What condition is associated with ESPN p.Asp304Tyr (c.910G>T)?

ESPN p.Asp304Tyr (c.910G>T) is associated with sensorineural hearing loss disorder (ClinVar).

How common is ESPN p.Asp304Tyr (c.910G>T) in the general population?

ESPN p.Asp304Tyr (c.910G>T) is ultra-rare (popmax 0.0183%, mid) (gnomAD).

What do computational predictors say about ESPN p.Asp304Tyr (c.910G>T)?

AlphaMissense predicts ambiguous (score 0.4176) — an in-silico prediction, not a clinical call.

ESPN p.Asp304Tyr

c.910G>T · rs776386029 · VCV694651

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4176 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, mid)

Conditions

sensorineural hearing loss disorder

Computational evidence

Protein change
AlphaMissense	0.4176	ambiguous
REVEL	0.438	indeterminate
SaProt	LLR -11.70	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	32.0	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 0.0183% Middle Eastern · 1/5,462 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000618% 9/1,455,444 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0183%	5,462
Remaining individualsnot grpmax-eligible	0.00322%	31,072
South Asian	0.00111%	90,138
European (non-Finnish)	0.000424%	235,643

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.Asp304Tyr
Coding: c.910G>T
MANE Select: NM_031475
dbSNP: rs776386029
Type: single nucleotide variant
Location: chr1:6440985 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76

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

Disease context

sensorineural hearing loss disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESPN p.Asn717Ser Uncertain significance ★★ ⚠ 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
ESPN p.Ala610Pro Uncertain significance ★★ ⚠ same type
ESPN p.Ala624Thr 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-asp304tyr (accessed [today's date]).

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