Is RAG1 p.Ser601Ala (c.1801T>G) pathogenic?

RAG1 p.Ser601Ala (c.1801T>G) is classified Uncertain significance in RAG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-02). AlphaMissense: likely benign (0.3067); Very rare (popmax 8.48e-05%, nfe); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

How common is RAG1 p.Ser601Ala (c.1801T>G) in the general population?

RAG1 p.Ser601Ala (c.1801T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RAG1 p.Ser601Ala (c.1801T>G)?

AlphaMissense predicts likely benign (score 0.3067) — an in-silico prediction, not a clinical call.

RAG1 p.Ser601Ala

Q: What condition is associated with RAG1 p.Ser601Ala (c.1801T>G)?

RAG1 p.Ser601Ala (c.1801T>G) 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.1801T>G · rs145951370 · VCV950254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.3067	likely benign
REVEL	0.753	pathogenic-leaning
SaProt	LLR -8.24	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 2,313 bp · p 3.1e-06 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,894 alleles

Overall 6.84e-05% 1/1,461,888 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.Ser601Ala
Coding: c.1801T>G
MANE Select: NM_000448
dbSNP: rs145951370
Type: single nucleotide variant
Location: chr11:36575105 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68

Full RAG1 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

RAG1 p.Ala444Val Pathogenic ★★★ same condition
RAG1 p.Arg108Ter Pathogenic ★★★ same condition
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-ser601ala (accessed [today's date]).

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