Is ESPN p.Arg32His (c.95G>A) pathogenic?

ESPN p.Arg32His (c.95G>A) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-18). AlphaMissense: likely benign (0.1768); Ultra-rare (popmax 0.0751%, afr).

How common is ESPN p.Arg32His (c.95G>A) in the general population?

ESPN p.Arg32His (c.95G>A) is ultra-rare (popmax 0.0751%, afr) (gnomAD).

What do computational predictors say about ESPN p.Arg32His (c.95G>A)?

AlphaMissense predicts likely benign (score 0.1768) — an in-silico prediction, not a clinical call.

ESPN p.Arg32His

c.95G>A · rs1006453315 · VCV1373960

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0751%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1768	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -12.69	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.2	GERP -2.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	24.8	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 0.0751% African / African-American · 51/67,866 alleles

Filtering AF 0.0587% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0528%

Overall 0.00565% 83/1,469,266 alleles · ultra-rare exomes 56/1,317,188 · genomes 27/152,078 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0751%	1,331
Remaining individualsnot grpmax-eligible	0.046%	2,176
Admixed American	0.0122%	8,192
European (non-Finnish)	8.95e-05%	1,117,596

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.Arg32His
Coding: c.95G>A
MANE Select: NM_031475
dbSNP: rs1006453315
Type: single nucleotide variant
Location: chr1:6425050 (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

Similar variants

ESPN p.Arg32Cys 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
ESPN p.Ala610Pro Uncertain significance ★★ ⚠ same type
ESPN p.Ala624Thr 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-arg32his (accessed [today's date]).

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