Is ESPN p.Pro431Ala (c.1291C>G) pathogenic?

ESPN p.Pro431Ala (c.1291C>G) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-28). AlphaMissense: likely benign (0.0706); Absent from gnomAD v4.1.

How common is ESPN p.Pro431Ala (c.1291C>G) in the general population?

ESPN p.Pro431Ala (c.1291C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ESPN p.Pro431Ala (c.1291C>G)?

AlphaMissense predicts likely benign (score 0.0706) — an in-silico prediction, not a clinical call.

ESPN p.Pro431Ala

c.1291C>G · rs1434749087 · VCV1935103

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0706 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0706	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -8.90	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 4.4	GERP 1.2, phastCons 0.99
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	12.66	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ESPN
Protein: p.Pro431Ala
Coding: c.1291C>G
MANE Select: NM_031475
dbSNP: rs1434749087
Type: single nucleotide variant
Location: chr1:6445762 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 431: the 'disordered' region

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

Similar variants

ESPN p.Pro431= Likely benign ★★ same residue
ESPN p.Pro431fs 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

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-pro431ala (accessed [today's date]).

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