Is IL2RA p.Ser74= (c.222G>A) pathogenic?

IL2RA p.Ser74= (c.222G>A) is classified Likely benign in IL2RA (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). Ultra-rare (popmax 0.0329%, mid); Associated with immunodeficiency due to CD25 deficiency.

What condition is associated with IL2RA p.Ser74= (c.222G>A)?

IL2RA p.Ser74= (c.222G>A) is associated with immunodeficiency due to CD25 deficiency (ClinVar).

How common is IL2RA p.Ser74= (c.222G>A) in the general population?

IL2RA p.Ser74= (c.222G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is Immunodeficiency due to CD25 deficiency inherited?

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

IL2RA p.Ser74=

c.222G>A · rs751234465 · VCV1588777

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

immunodeficiency due to CD25 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.008	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.1
Overall
CADD	1.717	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00142% 23/1,614,104 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.005%	20,003
East Asian	0.00445%	22,449
African / African-American	0.004%	24,977
Finnishnot grpmax-eligible	0.00312%	32,021
South Asian	0.0022%	45,546
European (non-Finnish)	0.000763%	131,116

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.Ser74=
Coding: c.222G>A
MANE Select: NM_000417
dbSNP: rs751234465
Type: single nucleotide variant
Location: chr10:6025868 (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 74: a disulfide bond; a β-strand; the sushi 1 domain

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.Ser74Leu 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
IL2RA p.Arg56His 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-ser74 (accessed [today's date]).

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