Is ESPN p.Val759Gly (c.2276T>G) pathogenic?

ESPN p.Val759Gly (c.2276T>G) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-28). AlphaMissense: likely pathogenic (0.7111); Very rare (popmax 0.00811%, afr).

How common is ESPN p.Val759Gly (c.2276T>G) in the general population?

ESPN p.Val759Gly (c.2276T>G) is very rare (popmax 0.00811%, afr) (gnomAD).

What do computational predictors say about ESPN p.Val759Gly (c.2276T>G)?

AlphaMissense predicts likely pathogenic (score 0.7111) — an in-silico prediction, not a clinical call.

ESPN p.Val759Gly

c.2276T>G · rs867461245 · VCV1493930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00811%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7111	likely pathogenic
REVEL	0.744	pathogenic-leaning
SaProt	LLR -11.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.61, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00811% African / African-American · 6/73,982 alleles

Filtering AF 0.00351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000635% 10/1,575,478 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00811%	12,330
Admixed American	0.00544%	18,399
Remaining individualsnot grpmax-eligible	0.00164%	61,006

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.Val759Gly
Coding: c.2276T>G
MANE Select: NM_031475
dbSNP: rs867461245
Type: single nucleotide variant
Location: chr1:6452047 (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.Val759Leu 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-val759gly (accessed [today's date]).

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