Is ESPN p.Glu752Lys (c.2254G>A) pathogenic?

ESPN p.Glu752Lys (c.2254G>A) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely pathogenic (0.7943); Very rare (popmax 0.00403%, afr).

How common is ESPN p.Glu752Lys (c.2254G>A) in the general population?

ESPN p.Glu752Lys (c.2254G>A) is very rare (popmax 0.00403%, afr) (gnomAD).

What do computational predictors say about ESPN p.Glu752Lys (c.2254G>A)?

AlphaMissense predicts likely pathogenic (score 0.7943) — an in-silico prediction, not a clinical call.

ESPN p.Glu752Lys

c.2254G>A · VCV4934063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7943 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00403%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7943	likely pathogenic
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -9.49	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, 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

Grpmax group 0.00403% African / African-American · 3/74,376 alleles

Filtering AF 0.00234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00204%

Overall 0.0027% 43/1,591,646 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00403%	24,792
South Asian	0.0034%	29,382
European (non-Finnish)	0.00317%	31,580

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.Glu752Lys
Coding: c.2254G>A
MANE Select: NM_031475
Type: single nucleotide variant
Location: chr1:6452025 (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

Similar variants

ESPN p.Glu752= Likely benign ★★ same residue
ESPN p.Glu752Gln Uncertain significance ★ ⚠ same residue
ESPN p.Glu752fs Pathogenic ★ same residue
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-glu752lys (accessed [today's date]).

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