Is RAG2 p.Pro180Ser (c.538C>T) pathogenic?

RAG2 p.Pro180Ser (c.538C>T) is classified Uncertain significance in RAG2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-03-24). AlphaMissense: likely pathogenic (0.575); Absent from gnomAD v4.1; Associated with Omenn syndrome.

What condition is associated with RAG2 p.Pro180Ser (c.538C>T)?

RAG2 p.Pro180Ser (c.538C>T) is associated with Omenn syndrome (ClinVar).

How common is RAG2 p.Pro180Ser (c.538C>T) in the general population?

RAG2 p.Pro180Ser (c.538C>T) is absent from gnomAD v4.1 (gnomAD).

How is Omenn syndrome inherited?

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

What do computational predictors say about RAG2 p.Pro180Ser (c.538C>T)?

AlphaMissense predicts likely pathogenic (score 0.575) — an in-silico prediction, not a clinical call.

RAG2 p.Pro180Ser

c.538C>T · VCV4060686

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.575 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Omenn syndrome

Computational evidence

Protein change
AlphaMissense	0.575	likely pathogenic
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -9.34	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,580 bp · p 0.79 · regional, not allelic
Overall
CADD	26.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RAG2
Protein: p.Pro180Ser
Coding: c.538C>T
MANE Select: NM_000536
Type: single nucleotide variant
Location: chr11:36593631 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 75.98 · 1 PDB

Full RAG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Omenn syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Omenn syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

RAG2 p.Pro180His Pathogenic/Likely pathogenic ★★ same residue
RAG2 p.Arg229Gln Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg229Trp Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg39Gly Pathogenic ★★★ ⚠ same condition
RAG2 p.Arg73Cys Likely pathogenic ★★★ ⚠ same condition
RAG2 p.Asp65Tyr Likely pathogenic ★★★ ⚠ same condition
RAG2 p.Glu437Lys Likely pathogenic ★★★ ⚠ same condition
RAG2 p.Gly319Ter Likely 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/rag2-p-pro180ser (accessed [today's date]).

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