Is IL2RA p.Ser166= (c.498C>T) pathogenic?

IL2RA p.Ser166= (c.498C>T) is classified Likely benign in IL2RA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-24). Ultra-rare (popmax 0.015%, amr); Associated with immunodeficiency due to CD25 deficiency.

What condition is associated with IL2RA p.Ser166= (c.498C>T)?

IL2RA p.Ser166= (c.498C>T) is associated with immunodeficiency due to CD25 deficiency (ClinVar).

How common is IL2RA p.Ser166= (c.498C>T) in the general population?

IL2RA p.Ser166= (c.498C>T) is ultra-rare (popmax 0.015%, amr) (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.Ser166=

c.498C>T · rs747017654 · VCV750398

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Conditions

immunodeficiency due to CD25 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.9	GERP -4.4
Overall
CADD	3.007	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/60,020 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.0013% 19/1,461,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,669
European (non-Finnish)	0.000847%	118,001

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.Ser166=
Coding: c.498C>T
MANE Select: NM_000417
dbSNP: rs747017654
Type: single nucleotide variant
Location: chr10:6021563 (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 166: a disulfide bond; a UniProt-annotated variant site (in imd41; the receptor does not localize to the plasma membrane); a β-strand; the sushi 2 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.Ser166Asn Pathogenic 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-ser166 (accessed [today's date]).

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