Is ESPN p.Ser232Arg (c.694A>C) pathogenic?

ESPN p.Ser232Arg (c.694A>C) is classified Uncertain significance in ESPN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: ambiguous (0.3683); Very rare (popmax 0.000367%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Ser232Arg (c.694A>C)?

ESPN p.Ser232Arg (c.694A>C) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Ser232Arg (c.694A>C) in the general population?

ESPN p.Ser232Arg (c.694A>C) is very rare (popmax 0.000367%, nfe) (gnomAD).

What do computational predictors say about ESPN p.Ser232Arg (c.694A>C)?

AlphaMissense predicts ambiguous (score 0.3683) — an in-silico prediction, not a clinical call.

ESPN p.Ser232Arg

c.694A>C · VCV3846237

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3683 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000367%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3683	ambiguous
REVEL	0.093	moderately benign-leaning
SaProt	LLR -7.17	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP -2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	23.8	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 0.000367% European (non-Finnish) · 3/818,550 alleles

Filtering AF 9.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.7e-05%

Overall 0.000312% 3/961,814 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.Ser232Arg
Coding: c.694A>C
MANE Select: NM_031475
Type: single nucleotide variant
Location: chr1:6440644 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76

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-ser232arg (accessed [today's date]).

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