Is ESPN p.Ala457Ser (c.1369G>T) pathogenic?

ESPN p.Ala457Ser (c.1369G>T) is classified Conflicting classifications of pathogenicity in ESPN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-05-14). AlphaMissense: likely benign (0.1601); Ultra-rare (popmax 0.0761%, eas); Associated with Usher syndrome, type 1M.

What condition is associated with ESPN p.Ala457Ser (c.1369G>T)?

ESPN p.Ala457Ser (c.1369G>T) is associated with Usher syndrome, type 1M, autosomal recessive nonsyndromic hearing loss 36 (ClinVar).

How common is ESPN p.Ala457Ser (c.1369G>T) in the general population?

ESPN p.Ala457Ser (c.1369G>T) is ultra-rare (popmax 0.0761%, eas) (gnomAD).

What do computational predictors say about ESPN p.Ala457Ser (c.1369G>T)?

AlphaMissense predicts likely benign (score 0.1601) — an in-silico prediction, not a clinical call.

ESPN p.Ala457Ser

c.1369G>T · rs370388560 · VCV2071078

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1601 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0761%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Usher syndrome, type 1M

Computational evidence

Protein change
AlphaMissense	0.1601	likely benign
REVEL	0.375	indeterminate
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.26	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 9.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 3,146 bp · p 3.4e-10 · regional, not allelic
Overall
CADD	22.9	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 0.0761% East Asian · 32/42,030 alleles

Filtering AF 0.0553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0483%

Overall 0.0215% 335/1,556,982 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0761%	1,313
Admixed American	0.0327%	3,058
European (non-Finnish)	0.0223%	4,491
Middle Eastern	0.0175%	5,718
South Asian	0.0156%	6,418
Remaining individualsnot grpmax-eligible	0.015%	6,660
African / African-American	0.00592%	16,890
Finnishnot grpmax-eligible	0.00173%	57,942

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.Ala457Ser
Coding: c.1369G>T
MANE Select: NM_031475
dbSNP: rs370388560
Type: single nucleotide variant
Location: chr1:6445840 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 457: the 'disordered' region

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

Disease context

Usher syndrome, type 1M — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 36

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.Ser342Phe 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-ala457ser (accessed [today's date]).

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