Is RAG1 p.Phe5Leu (c.15C>G) pathogenic?

RAG1 p.Phe5Leu (c.15C>G) is classified Uncertain significance in RAG1 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-04-23). AlphaMissense: likely benign (0.1961); Very rare (popmax 0.000847%, nfe); Associated with recombinase activating gene 1 deficiency.

How common is RAG1 p.Phe5Leu (c.15C>G) in the general population?

RAG1 p.Phe5Leu (c.15C>G) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about RAG1 p.Phe5Leu (c.15C>G)?

AlphaMissense predicts likely benign (score 0.1961) — an in-silico prediction, not a clinical call.

RAG1 p.Phe5Leu

Q: What condition is associated with RAG1 p.Phe5Leu (c.15C>G)?

RAG1 p.Phe5Leu (c.15C>G) 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.15C>G · rs745600099 · VCV971195

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

recombinase activating gene 1 deficiency

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

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

PM2_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000448.3:c.15C>G variant in RAG1 is a missense variant predicted to cause a substitution of phenylalanine by leucine at amino acid 5 (p.Phe5Leu). The Popmax filtering allele frequency of this variant in gnomAD v2.1.1 is 0.00000292, which is lower than the SCID-VCEP’s threshold for PM2 (<0.000102). No homozygous individual has been observed in the gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one affected individual who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV001420312.4). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0).

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

Computational evidence

Protein change
AlphaMissense	0.1961	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -4.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 0.43, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 814 bp · p 0.066 · regional, not allelic
Overall
CADD	11.25	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.000847% European (non-Finnish) · 10/1,180,026 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,040 alleles · very rare

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.Phe5Leu
Coding: c.15C>G
MANE Select: NM_000448
dbSNP: rs745600099
Type: single nucleotide variant
Location: chr11:36573319 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 5: 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

Similar variants

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RAG1 p.Arg142Ter 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
RAG1 p.Arg561Cys 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-phe5leu (accessed [today's date]).

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