Is ESPN p.Arg113His (c.338G>A) pathogenic?

ESPN p.Arg113His (c.338G>A) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-06). AlphaMissense: ambiguous (0.4648); Ultra-rare (popmax 0.0103%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Arg113His (c.338G>A)?

ESPN p.Arg113His (c.338G>A) is associated with Inborn genetic diseases, inherited retinal dystrophy (ClinVar).

How common is ESPN p.Arg113His (c.338G>A) in the general population?

ESPN p.Arg113His (c.338G>A) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about ESPN p.Arg113His (c.338G>A)?

AlphaMissense predicts ambiguous (score 0.4648) — an in-silico prediction, not a clinical call.

ESPN p.Arg113His

c.338G>A · rs367832657 · VCV1254240

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4648 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4648	ambiguous
REVEL	0.461	indeterminate
SaProt	LLR -6.71	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	33.0	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 0.0103% European (non-Finnish) · 122/1,179,998 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00828%

Overall 0.00843% 136/1,613,524 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,672
East Asian	0.00892%	11,216
Admixed American	0.00333%	30,011
South Asian	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0032%	31,248
Finnishnot grpmax-eligible	0.00315%	31,726
African / African-American	0.00133%	75,026

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.Arg113His
Coding: c.338G>A
MANE Select: NM_031475
dbSNP: rs367832657
Type: single nucleotide variant
Location: chr1:6428269 (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

Also linked: inherited retinal dystrophy

Similar variants

ESPN p.Arg113Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ESPN p.Arg113Leu 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.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-arg113his (accessed [today's date]).

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