Is ESPN p.Arg632Cys (c.1894C>T) pathogenic?

ESPN p.Arg632Cys (c.1894C>T) is classified Benign/Likely benign in ESPN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.2521); Rare (popmax 0.823%, sas).

How common is ESPN p.Arg632Cys (c.1894C>T) in the general population?

ESPN p.Arg632Cys (c.1894C>T) is rare (popmax 0.823%, sas) (gnomAD).

What do computational predictors say about ESPN p.Arg632Cys (c.1894C>T)?

AlphaMissense predicts likely benign (score 0.2521) — an in-silico prediction, not a clinical call.

ESPN p.Arg632Cys

c.1894C>T · rs543768706 · VCV1182246

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2521 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.823%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2521	likely benign
REVEL	0.393	indeterminate
SaProt	LLR -8.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.7 · regional, not allelic
Overall
CADD	28.3	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 0.823% South Asian · 645/78,392 alleles

Filtering AF 0.77% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.749%

Overall 0.0462% 685/1,483,524 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.823%	122
Remaining individualsnot grpmax-eligible	0.0574%	1,741
Middle Eastern	0.0236%	4,238
Admixed American	0.00449%	22,270
African / African-American	0.00291%	34,411
European (non-Finnish)	0.000178%	562,035

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.Arg632Cys
Coding: c.1894C>T
MANE Select: NM_031475
dbSNP: rs543768706
Type: single nucleotide variant
Location: chr1:6449070 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 632: the 'disordered' region

Full ESPN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESPN p.Arg632_Ser633delinsPro 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-arg632cys (accessed [today's date]).

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