Is ESPN p.Val677Met (c.2029G>A) pathogenic?

ESPN p.Val677Met (c.2029G>A) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-18). AlphaMissense: ambiguous (0.4134); Ultra-rare (popmax 0.03%, amr); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Val677Met (c.2029G>A)?

ESPN p.Val677Met (c.2029G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Val677Met (c.2029G>A) in the general population?

ESPN p.Val677Met (c.2029G>A) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about ESPN p.Val677Met (c.2029G>A)?

AlphaMissense predicts ambiguous (score 0.4134) — an in-silico prediction, not a clinical call.

ESPN p.Val677Met

c.2029G>A · rs777091021 · VCV3090486

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4134 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4134	ambiguous
REVEL	0.502	indeterminate
SaProt	LLR -7.81	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	28.6	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 0.03% Admixed American · 18/59,956 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00291% 47/1,612,798 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,331
African / African-American	0.0294%	3,406
Remaining individualsnot grpmax-eligible	0.0112%	8,919

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.Val677Met
Coding: c.2029G>A
MANE Select: NM_031475
dbSNP: rs777091021
Type: single nucleotide variant
Location: chr1:6451716 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 677: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESPN p.Val677Glu Uncertain significance ★ same residue
ESPN p.Val677= Likely benign ★ same residue
ESPN p.Ala139Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala23Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala484Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala729Glu Uncertain significance ★★ ⚠ same condition
ESPN p.Arg113His Uncertain significance ★★ ⚠ same condition
ESPN p.Arg335Cys Uncertain significance ★★ ⚠ same condition

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-val677met (accessed [today's date]).

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