Is RAG1 p.Arg142Ter (c.424C>T) pathogenic?

RAG1 p.Arg142Ter (c.424C>T) is classified Pathogenic in RAG1 (ClinVar, Expert panel, 8 submitters; last evaluated 2023-11-14). Very rare (popmax 0.00333%, amr); Associated with recombinase activating gene 1 deficiency.

How common is RAG1 p.Arg142Ter (c.424C>T) in the general population?

RAG1 p.Arg142Ter (c.424C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

RAG1 p.Arg142Ter

Q: What condition is associated with RAG1 p.Arg142Ter (c.424C>T)?

RAG1 p.Arg142Ter (c.424C>T) is associated with recombinase activating gene 1 deficiency, combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

c.424C>T · rs773929270 · VCV626157

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

recombinase activating gene 1 deficiency

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

Pathogenic for recombinase activating gene 1 deficiency. Applied ACMG criteria (verbatim):

PVS1 PM2_Supporting PM3

Curation rationale (ClinGen, verbatim)

The nonsense variant NM_000448.3(RAG1):c.424C>T (p.Arg142Ter) occurs in exon 2 of 2 (the only coding exon of RAG1) and is not predicted to result in nonsense-mediated decay but does truncate 86% of the protein, including the entirety of the core domain (amino acids 387-1011) which is critical to protein function (PMID: 26996199; PVS1). The popmax allele frequency is 0.00004007 (1/24954 alleles) in the African/African American population, which is below the SCID VCEP established threshold of <0.000102 (PM2_supporting). This variant has been reported in at least seven patients with atypical SCID or Omenn syndrome (PMIDs: 30877075, 33225392, 30307608, 25849362, 20109747, 24290284, 17075247) however in all cases there is insufficient information to determine that the patient's phenotype is highly specific to recombinase activating gene 1 deficiency (PP4_NotMet). This variant has been reported homozygous in at least two Omenn syndrome patients (PMIDs: 33225392, 30307608; 1pt; PM3). Five additional atypical SCID or Omenn syndrome cases have been reported compound heterozygous for this variant (PMIDs: 30877075, 25849362, 20109747, 24290284, 17075247). Functional studies have shown a deleterious effect of this variant, significantly reducing function of the V(D)J recombination activity; mean recombination activity for Arg142Ter was 9.0% of wild type +/- 4.0 (PMID: 24290284). However, because no patient has been identified meeting the PP4 criteria PS3 is not applied at any strength. In summary, this variant meets the criteria to be classified as pathogenic for recombinase activating gene 1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM3 and PM2_Supporting. (VCEP specifications version 1).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	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 · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.87	GERP 0.65, phastCons 0.98
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,990 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000929% 15/1,613,816 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,995
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00134%	74,896
European (non-Finnish)	0.000847%	118,003

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: RAG1
Protein: p.Arg142Ter
Coding: c.424C>T
MANE Select: NM_000448
dbSNP: rs773929270
Type: single nucleotide variant
Location: chr11:36573728 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 142: the 'interaction with importin alpha-1' region

Full RAG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

recombinase activating gene 1 deficiency — 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 Omenn syndrome combined immunodeficiency due to partial RAG1 deficiency

Similar variants

RAG1 p.Arg142Gln Uncertain significance ★ ⚠ same residue
RAG1 p.Arg142= Likely benign ★ same residue
RAG1 p.Ala444Val Pathogenic ★★★ same condition
RAG1 p.Arg108Ter Pathogenic ★★★ same condition
RAG1 p.Arg394Gln Likely pathogenic ★★★ same condition
RAG1 p.Arg394Trp Pathogenic ★★★ same condition
RAG1 p.Arg396His Pathogenic ★★★ same condition
RAG1 p.Arg404Gln 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/rag1-p-arg142ter (accessed [today's date]).

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