Is ESPN p.Arg782Leu (c.2345G>T) pathogenic?

ESPN p.Arg782Leu (c.2345G>T) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-22). AlphaMissense: likely benign (0.2697); Very rare (popmax 8.49e-05%, nfe).

How common is ESPN p.Arg782Leu (c.2345G>T) in the general population?

ESPN p.Arg782Leu (c.2345G>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about ESPN p.Arg782Leu (c.2345G>T)?

AlphaMissense predicts likely benign (score 0.2697) — an in-silico prediction, not a clinical call.

ESPN p.Arg782Leu

c.2345G>T · rs764608871 · VCV2504294

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2697	likely benign
REVEL	0.433	indeterminate
SaProt	LLR -12.21	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	25.1	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 8.49e-05% European (non-Finnish) · 1/1,177,262 alleles

Overall 6.87e-05% 1/1,456,024 alleles · very 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.Arg782Leu
Coding: c.2345G>T
MANE Select: NM_031475
dbSNP: rs764608871
Type: single nucleotide variant
Location: chr1:6457203 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 782: the 'disordered' region

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

Similar variants

ESPN p.Arg782Gln Uncertain significance ★★ ⚠ same residue
ESPN p.Arg782Pro Uncertain significance ★★ ⚠ same residue
ESPN p.Arg782Trp 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

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-arg782leu (accessed [today's date]).

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