Is IL2RG p.Cys72Phe (c.215G>T) pathogenic?

IL2RG p.Cys72Phe (c.215G>T) is classified Uncertain significance in IL2RG (ClinVar, Single submitter, 1 submitter; last evaluated 2017-06-21). AlphaMissense: likely pathogenic (0.9472); Absent from gnomAD v4.1; Associated with T-B+ severe combined immunodeficiency due to gamma chain deficiency.

What condition is associated with IL2RG p.Cys72Phe (c.215G>T)?

IL2RG p.Cys72Phe (c.215G>T) is associated with T-B+ severe combined immunodeficiency due to gamma chain deficiency (ClinVar).

How common is IL2RG p.Cys72Phe (c.215G>T) in the general population?

IL2RG p.Cys72Phe (c.215G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IL2RG p.Cys72Phe (c.215G>T)?

AlphaMissense predicts likely pathogenic (score 0.9472) — an in-silico prediction, not a clinical call.

IL2RG p.Cys72Phe

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.215G>T · rs1556330960 · VCV463380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9472 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9472	likely pathogenic · top 4% in IL2RG
REVEL	0.922	moderately pathogenic-leaning
SaProt	LLR -11.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 2,218 bp · p 0.0001 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IL2RG
Protein: p.Cys72Phe
Coding: c.215G>T
MANE Select: NM_000206
dbSNP: rs1556330960
Type: single nucleotide variant
Location: chrX:71110951 (GRCh38)
Structure: AlphaFold pLDDT 76.75 · 14 PDB
Residue 72: a disulfide bond; 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.Cys72Ter Likely pathogenic ★★★ same residue
IL2RG p.Cys72= Likely benign ★ 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

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-cys72phe (accessed [today's date]).

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