Is ESPN p.Arg113Cys (c.337C>T) pathogenic?

ESPN p.Arg113Cys (c.337C>T) is classified Conflicting classifications of pathogenicity in ESPN (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-03-01). AlphaMissense: ambiguous (0.5274); Rare (popmax 0.248%, mid); Associated with inherited retinal dystrophy.

What condition is associated with ESPN p.Arg113Cys (c.337C>T)?

ESPN p.Arg113Cys (c.337C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is ESPN p.Arg113Cys (c.337C>T) in the general population?

ESPN p.Arg113Cys (c.337C>T) is rare (popmax 0.248%, mid) (gnomAD).

What do computational predictors say about ESPN p.Arg113Cys (c.337C>T)?

AlphaMissense predicts ambiguous (score 0.5274) — an in-silico prediction, not a clinical call.

ESPN p.Arg113Cys

c.337C>T · rs143577178 · VCV228670

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5274 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.248%, mid)

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.5274	ambiguous
REVEL	0.448	indeterminate
SaProt	LLR -8.96	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	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 0.248% Middle Eastern · 15/6,060 alleles

Filtering AF 0.152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.0315% 508/1,613,588 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.248%	404
Admixed American	0.122%	822
Remaining individualsnot grpmax-eligible	0.0784%	1,276
South Asian	0.0758%	1,320
European (non-Finnish)	0.0241%	4,155
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,921
African / African-American	0.0107%	9,383
Finnishnot grpmax-eligible	0.00788%	12,695

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.Arg113Cys
Coding: c.337C>T
MANE Select: NM_031475
dbSNP: rs143577178
Type: single nucleotide variant
Location: chr1:6428268 (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

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESPN p.Arg113His Uncertain significance ★★ same residue
ESPN p.Arg113Leu Uncertain significance ★ ⚠ same residue
ESPN p.Arg335Cys Uncertain significance ★★ same condition
ESPN p.Ser312Leu Uncertain significance ★★ ⚠ same condition
ESPN p.Ser342Phe Uncertain significance ★★ ⚠ same condition
ESPN p.Val165Met Uncertain significance ★★ ⚠ same condition
ESPN c.858+11G>T Benign ★★ same condition
ESPN c.1464+2T>G Likely pathogenic 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-arg113cys (accessed [today's date]).

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