Is ESPN p.Glu776Lys (c.2326G>A) pathogenic?

ESPN p.Glu776Lys (c.2326G>A) is classified Likely benign in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely benign (0.1741); Rare (popmax 0.249%, eas).

How common is ESPN p.Glu776Lys (c.2326G>A) in the general population?

ESPN p.Glu776Lys (c.2326G>A) is rare (popmax 0.249%, eas) (gnomAD).

What do computational predictors say about ESPN p.Glu776Lys (c.2326G>A)?

AlphaMissense predicts likely benign (score 0.1741) — an in-silico prediction, not a clinical call.

ESPN p.Glu776Lys

c.2326G>A · VCV4934212

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1741 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.249%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1741	likely benign
REVEL	0.368	indeterminate
SaProt	LLR -4.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.76	acceptor gain · deltas
Pangolin	Δ0.36	gain · loss 0.02 · agrees with SpliceAI · independent
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	36.0	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 0.249% East Asian · 109/43,764 alleles

Filtering AF 0.211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.197%

Overall 0.00699% 111/1,587,466 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.249%	402
Remaining individualsnot grpmax-eligible	0.00325%	30,736

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.Glu776Lys
Coding: c.2326G>A
MANE Select: NM_031475
Type: single nucleotide variant
Location: chr1:6457184 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 776: the 'disordered' region

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

Similar variants

ESPN p.Glu776Asp Uncertain significance ★★ ⚠ 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
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-glu776lys (accessed [today's date]).

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