Is ESPN p.Val543Gly (c.1628T>G) pathogenic?

ESPN p.Val543Gly (c.1628T>G) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-08). AlphaMissense: likely benign (0.0955); Ultra-rare (popmax 0.048%, afr); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Val543Gly (c.1628T>G)?

ESPN p.Val543Gly (c.1628T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Val543Gly (c.1628T>G) in the general population?

ESPN p.Val543Gly (c.1628T>G) is ultra-rare (popmax 0.048%, afr) (gnomAD).

What do computational predictors say about ESPN p.Val543Gly (c.1628T>G)?

AlphaMissense predicts likely benign (score 0.0955) — an in-silico prediction, not a clinical call.

ESPN p.Val543Gly

c.1628T>G · rs954222909 · VCV1506781

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0955 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0955	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -5.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ1.00	donor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 3,146 bp · p 3.4e-10 · regional, not allelic
Overall
CADD	23.8	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 0.048% African / African-American · 31/64,556 alleles

Filtering AF 0.0347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.00239% 31/1,296,572 alleles · ultra-rare

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.Val543Gly
Coding: c.1628T>G
MANE Select: NM_031475
dbSNP: rs954222909
Type: single nucleotide variant
Location: chr1:6448804 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 543: 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.Val543Met Uncertain significance ★ ⚠ 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
ESPN p.Arg339Gln 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-val543gly (accessed [today's date]).

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