Is RAG2 p.Ile228= (c.684C>T) pathogenic?

RAG2 p.Ile228= (c.684C>T) is classified Likely benign in RAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-07). Very rare (popmax 0.00328%); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

How common is RAG2 p.Ile228= (c.684C>T) in the general population?

RAG2 p.Ile228= (c.684C>T) is very rare (popmax 0.00328%) (gnomAD).

RAG2 p.Ile228=

Q: What condition is associated with RAG2 p.Ile228= (c.684C>T)?

RAG2 p.Ile228= (c.684C>T) is associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, combined immunodeficiency with skin granulomas (ClinVar).

Q: How is Severe combined immunodeficiency due to complete RAG1/2 deficiency inherited?

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

c.684C>T · rs145031483 · VCV2937155

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00328%)

Conditions

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP -1.9, phastCons 1
Overall
CADD	4.446	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00328%

Overall 0.00328% 53/1,613,896 alleles · very rare exomes 49/1,461,746 · genomes 4/152,150 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0798%	1,253
Remaining individualsnot grpmax-eligible	0.0032%	31,244

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: RAG2
Protein: p.Ile228=
Coding: c.684C>T
MANE Select: NM_000536
dbSNP: rs145031483
Type: single nucleotide variant
Location: chr11:36593485 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 75.98 · 1 PDB

Full RAG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined immunodeficiency with skin granulomas

For Severe combined immunodeficiency due to complete RAG1/2 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RAG2 p.Ile228Phe Uncertain significance ★ ⚠ same residue
RAG2 p.Ile228fs Likely pathogenic ★ same residue
RAG2 p.Arg229Gln Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg229Trp Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg39Gly Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg73Cys Likely pathogenic ★★★ ⚠ same condition
RAG2 p.Asp65Tyr Likely pathogenic ★★★ ⚠ same condition
RAG2 p.Cys446Trp Likely 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/rag2-p-ile228 (accessed [today's date]).

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