Is RAG1 p.Pro284Ser (c.850C>T) pathogenic?

RAG1 p.Pro284Ser (c.850C>T) is classified Uncertain significance in RAG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-17). AlphaMissense: likely pathogenic (0.7123); Ultra-rare (popmax 0.0283%, amr); Associated with combined immunodeficiency with skin granulomas.

What condition is associated with RAG1 p.Pro284Ser (c.850C>T)?

RAG1 p.Pro284Ser (c.850C>T) is associated with combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (ClinVar).

How common is RAG1 p.Pro284Ser (c.850C>T) in the general population?

RAG1 p.Pro284Ser (c.850C>T) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

How is Combined immunodeficiency with granulomatosis inherited?

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

What do computational predictors say about RAG1 p.Pro284Ser (c.850C>T)?

AlphaMissense predicts likely pathogenic (score 0.7123) — an in-silico prediction, not a clinical call.

RAG1 p.Pro284Ser

c.850C>T · rs768862261 · VCV1057692

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7123 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency with skin granulomas

Computational evidence

Protein change
AlphaMissense	0.7123	likely pathogenic
REVEL	0.76	pathogenic-leaning
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 2,313 bp · p 3.1e-06 · regional, not allelic
Overall
CADD	23.1	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 0.0283% Admixed American · 17/60,020 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00112% 18/1,614,192 alleles · ultra-rare exomes 18/1,461,892 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,531
European (non-Finnish)	8.47e-05%	1,180,043

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.Pro284Ser
Coding: c.850C>T
MANE Select: NM_000448
dbSNP: rs768862261
Type: single nucleotide variant
Location: chr11:36574154 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 284: the 'interaction with importin alpha-1' region

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

Disease context

combined immunodeficiency with skin granulomas — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Combined immunodeficiency with granulomatosis (Orphanet):

Inheritance: Autosomal recessive

Similar variants

RAG1 p.Pro284Leu Uncertain significance ★ ⚠ same residue
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

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-pro284ser (accessed [today's date]).

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