Is RAG1 p.Ala857= (c.2571C>T) pathogenic?

RAG1 p.Ala857= (c.2571C>T) is classified Conflicting classifications of pathogenicity in RAG1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-05-01). Rare (popmax 0.393%, nfe); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive.

How common is RAG1 p.Ala857= (c.2571C>T) in the general population?

RAG1 p.Ala857= (c.2571C>T) is rare (popmax 0.393%, nfe) (gnomAD).

RAG1 p.Ala857=

Q: What condition is associated with RAG1 p.Ala857= (c.2571C>T)?

RAG1 p.Ala857= (c.2571C>T) is associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, combined immunodeficiency with skin granulomas, Omenn syndrome (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.2571C>T · rs141560248 · VCV469113

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.393%, nfe)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.9, phastCons 1
Overall
CADD	16.59	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.393% European (non-Finnish) · 4,632/1,180,042 alleles

Filtering AF 0.383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.379%

Overall 0.337% 5,441/1,614,172 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.393%	255
Finnishnot grpmax-eligible	0.344%	291
South Asian	0.301%	332
Remaining individualsnot grpmax-eligible	0.29%	345
Middle Eastern	0.148%	674
Ashkenazi Jewishnot grpmax-eligible	0.101%	987
Admixed American	0.0949%	1,053
African / African-American	0.0506%	1,975

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.Ala857=
Coding: c.2571C>T
MANE Select: NM_000448
dbSNP: rs141560248
Type: single nucleotide variant
Location: chr11:36575875 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68
Residue 857: a UniProt-annotated variant site (in t(-)b(-)nk(+) scid; uncertain significance)

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 Omenn syndrome

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.Ala857Val 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-ala857 (accessed [today's date]).

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