Is IL2RG p.Pro229= (c.687A>G) pathogenic?

IL2RG p.Pro229= (c.687A>G) is classified Likely benign in IL2RG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-20). Very rare (popmax 0.000112%, nfe); Associated with T-B+ severe combined immunodeficiency due to gamma chain deficiency.

What condition is associated with IL2RG p.Pro229= (c.687A>G)?

IL2RG p.Pro229= (c.687A>G) is associated with T-B+ severe combined immunodeficiency due to gamma chain deficiency (ClinVar).

How common is IL2RG p.Pro229= (c.687A>G) in the general population?

IL2RG p.Pro229= (c.687A>G) is very rare (popmax 0.000112%, nfe) (gnomAD).

IL2RG p.Pro229=

Q: How is T-B+ severe combined immunodeficiency due to gamma chain deficiency inherited?

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

c.687A>G · rs2519645572 · VCV2811920

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Conditions

T-B+ severe combined immunodeficiency due to gamma chain deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.073	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.9	GERP -3
Overall
CADD	6.213	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000112% European (non-Finnish) · 1/894,418 alleles

Overall 8.26e-05% 1/1,210,186 alleles · very rare exomes 1/1,097,241 · genomes 0/112,945 · joint denominator

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: IL2RG
Protein: p.Pro229=
Coding: c.687A>G
MANE Select: NM_000206
dbSNP: rs2519645572
Type: single nucleotide variant
Location: chrX:71109298 (GRCh38)
Structure: AlphaFold pLDDT 76.75 · 14 PDB
Residue 229: the fibronectin type-iii domain; a β-strand

Full IL2RG gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

T-B+ severe combined immunodeficiency due to gamma chain deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For T-B+ severe combined immunodeficiency due to gamma chain deficiency (Orphanet):

Inheritance: X-linked recessive
Onset: Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

IL2RG p.Pro229Thr Uncertain significance ★ ⚠ same residue
IL2RG c.115+1G>T Pathogenic ★★★ same condition
IL2RG c.115+2T>C Pathogenic ★★★ same condition
IL2RG c.116-1G>A Pathogenic ★★★ same condition
IL2RG c.116-2A>G Likely pathogenic ★★★ same condition
IL2RG c.269+1G>T Pathogenic ★★★ same condition
IL2RG c.455-2A>C Pathogenic ★★★ same condition
IL2RG c.455-2A>T 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/il2rg-p-pro229 (accessed [today's date]).

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