Is IL2RA p.Arg88Pro (c.263G>C) pathogenic?

IL2RA p.Arg88Pro (c.263G>C) is classified Uncertain significance in IL2RA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-03). AlphaMissense: likely benign (0.2011); Ultra-rare (popmax 0.0307%, afr); Associated with immunodeficiency due to CD25 deficiency.

What condition is associated with IL2RA p.Arg88Pro (c.263G>C)?

IL2RA p.Arg88Pro (c.263G>C) is associated with immunodeficiency due to CD25 deficiency (ClinVar).

How common is IL2RA p.Arg88Pro (c.263G>C) in the general population?

IL2RA p.Arg88Pro (c.263G>C) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

How is Immunodeficiency due to CD25 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about IL2RA p.Arg88Pro (c.263G>C)?

AlphaMissense predicts likely benign (score 0.2011) — an in-silico prediction, not a clinical call.

IL2RA p.Arg88Pro

c.263G>C · rs139340259 · VCV2180984

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2011 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency due to CD25 deficiency

Computational evidence

Protein change
AlphaMissense	0.2011	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -4.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.5	GERP -4.2
Regional constraint	o/e 0.92	unconstrained · MANE · 49 kb · p 0.11 · regional, not allelic
Overall
CADD	2.783	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0307% African / African-American · 23/74,810 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00155% 25/1,608,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,253
Admixed American	0.00334%	29,983

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: IL2RA
Protein: p.Arg88Pro
Coding: c.263G>C
MANE Select: NM_000417
dbSNP: rs139340259
Type: single nucleotide variant
Location: chr10:6024348 (GRCh38)
Gene constraint: LOEUF 0.906 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.72 · 10 PDB
Residue 88: a disulfide bond; the 'disordered' region

Full IL2RA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency due to CD25 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to CD25 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

IL2RA p.Arg88Gln Uncertain significance ★★ ⚠ same residue
IL2RA p.Arg88Trp Uncertain significance ★★ ⚠ same residue
IL2RA p.Gln101Ter Pathogenic ★★ same condition
IL2RA c.655+4C>T Uncertain significance ★★ same condition
IL2RA c.*1026G>T Uncertain significance ★★ same condition
IL2RA p.Arg206Cys Uncertain significance ★★ ⚠ same condition
IL2RA p.Arg206His Uncertain significance ★★ ⚠ same condition
IL2RA p.Arg263Trp 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/il2ra-p-arg88pro (accessed [today's date]).

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