Is RAG2 p.Phe378fs (c.1131del) pathogenic?

RAG2 p.Phe378fs (c.1131del) is classified Pathogenic/Likely pathogenic in RAG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-03). No gnomAD frequency available for this variant; Associated with Omenn syndrome.

How common is RAG2 p.Phe378fs (c.1131del) in the general population?

RAG2 p.Phe378fs (c.1131del) is no gnomAD frequency available for this variant (gnomAD).

How is Omenn syndrome inherited?

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

RAG2 p.Phe378fs

Q: What condition is associated with RAG2 p.Phe378fs (c.1131del)?

RAG2 p.Phe378fs (c.1131del) is associated with Omenn syndrome, combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

c.1131del · rs2494790291 · VCV2939601

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Omenn syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.4	GERP 2.7, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RAG2
Protein: p.Phe378fs
Coding: c.1131del
MANE Select: NM_000536
dbSNP: rs2494790291
Type: Deletion
Location: chr11:36593038 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 75.98 · 1 PDB
Residue 378: the 'disordered' region

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

Disease context

Omenn syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined immunodeficiency with skin granulomas severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

For Omenn syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

RAG2 p.Cys287fs Pathogenic ★★ same condition
RAG2 p.His468fs Pathogenic/Likely pathogenic ★★ same condition
RAG2 p.Leu129fs Pathogenic/Likely pathogenic ★★ same condition
RAG2 p.Asn101fs Likely pathogenic ★ same condition
RAG2 p.Asn248fs Pathogenic ★ same condition
RAG2 p.Asn288fs Pathogenic ★ same condition
RAG2 p.Asn364fs Likely pathogenic ★ same condition
RAG2 p.Asp450fs 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-phe378fs (accessed [today's date]).

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