Is ESPN p.Val223Leu (c.667G>C) pathogenic?

ESPN p.Val223Leu (c.667G>C) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-02). AlphaMissense: ambiguous (0.3898); Very rare (popmax 0.00235%, eas).

How common is ESPN p.Val223Leu (c.667G>C) in the general population?

ESPN p.Val223Leu (c.667G>C) is very rare (popmax 0.00235%, eas) (gnomAD).

What do computational predictors say about ESPN p.Val223Leu (c.667G>C)?

AlphaMissense predicts ambiguous (score 0.3898) — an in-silico prediction, not a clinical call.

ESPN p.Val223Leu

c.667G>C · rs1456264982 · VCV804795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3898 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00235%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3898	ambiguous
REVEL	0.119	moderately benign-leaning
SaProt	LLR -6.76	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	24.1	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 0.00235% East Asian · 1/42,560 alleles

Filtering AF 0.00116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000988%

Overall 0.0017% 24/1,413,340 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00235%	42,560
South Asian	0.00231%	43,292
European (non-Finnish)	0.00181%	55,183

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.Val223Leu
Coding: c.667G>C
MANE Select: NM_031475
dbSNP: rs1456264982
Type: single nucleotide variant
Location: chr1:6440432 (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.Val223= Likely benign ★ 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-val223leu (accessed [today's date]).

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