Is ESPN p.Ser504Arg (c.1512C>G) pathogenic?

ESPN p.Ser504Arg (c.1512C>G) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-06). AlphaMissense: likely benign (0.2133); Ultra-rare (popmax 0.0413%, amr); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Ser504Arg (c.1512C>G)?

ESPN p.Ser504Arg (c.1512C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Ser504Arg (c.1512C>G) in the general population?

ESPN p.Ser504Arg (c.1512C>G) is ultra-rare (popmax 0.0413%, amr) (gnomAD).

What do computational predictors say about ESPN p.Ser504Arg (c.1512C>G)?

AlphaMissense predicts likely benign (score 0.2133) — an in-silico prediction, not a clinical call.

ESPN p.Ser504Arg

c.1512C>G · rs763714861 · VCV2048400

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2133 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0413%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2133	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -7.18	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 2.5	GERP 0.21, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 3,146 bp · p 3.4e-10 · regional, not allelic
Overall
CADD	21.5	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 0.0413% Admixed American · 22/53,326 alleles

Filtering AF 0.0279% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0235%

Overall 0.00207% 32/1,545,404 alleles · ultra-rare exomes 31/1,393,254 · genomes 1/152,150 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0413%	2,424
European (non-Finnish)	0.000865%	115,667

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.Ser504Arg
Coding: c.1512C>G
MANE Select: NM_031475
dbSNP: rs763714861
Type: single nucleotide variant
Location: chr1:6448688 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 504: 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.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
ESPN p.Arg478Cys 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-ser504arg (accessed [today's date]).

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