Is ESPN p.Lys254Arg (c.761A>G) pathogenic?

ESPN p.Lys254Arg (c.761A>G) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-18). AlphaMissense: likely benign (0.1271); Very rare (popmax 0.00244%, eas).

How common is ESPN p.Lys254Arg (c.761A>G) in the general population?

ESPN p.Lys254Arg (c.761A>G) is very rare (popmax 0.00244%, eas) (gnomAD).

What do computational predictors say about ESPN p.Lys254Arg (c.761A>G)?

AlphaMissense predicts likely benign (score 0.1271) — an in-silico prediction, not a clinical call.

ESPN p.Lys254Arg

c.761A>G · rs2522813284 · VCV2499883

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1271 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00244%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1271	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -6.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9	GERP -2.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00244% East Asian · 1/41,064 alleles

Overall 0.000143% 2/1,394,642 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00244%	41,064
South Asian	0.00119%	83,764

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.Lys254Arg
Coding: c.761A>G
MANE Select: NM_031475
dbSNP: rs2522813284
Type: single nucleotide variant
Location: chr1:6440711 (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 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
ESPN p.Ala729Glu 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-lys254arg (accessed [today's date]).

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