Is ESPN p.Val721Ile (c.2161G>A) pathogenic?

ESPN p.Val721Ile (c.2161G>A) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-08). AlphaMissense: likely benign (0.0964); Very rare (popmax 0.00995%, sas).

How common is ESPN p.Val721Ile (c.2161G>A) in the general population?

ESPN p.Val721Ile (c.2161G>A) is very rare (popmax 0.00995%, sas) (gnomAD).

What do computational predictors say about ESPN p.Val721Ile (c.2161G>A)?

AlphaMissense predicts likely benign (score 0.0964) — an in-silico prediction, not a clinical call.

ESPN p.Val721Ile

c.2161G>A · rs753791831 · VCV1474609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00995%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0964	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -7.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	17.52	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 0.00995% South Asian · 9/90,418 alleles

Filtering AF 0.00517% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.000686% 10/1,458,492 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00995%	10,046
European (non-Finnish)	8.48e-05%	1,178,842

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.Val721Ile
Coding: c.2161G>A
MANE Select: NM_031475
dbSNP: rs753791831
Type: single nucleotide variant
Location: chr1:6451932 (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-val721ile (accessed [today's date]).

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