Is RASGRP1 p.Pro441Ser (c.1321C>T) pathogenic?

RASGRP1 p.Pro441Ser (c.1321C>T) is classified Uncertain significance in RASGRP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-09). AlphaMissense: likely benign (0.0989); Very rare (popmax 0.00223%, eas); Associated with immunodeficiency 64.

What condition is associated with RASGRP1 p.Pro441Ser (c.1321C>T)?

RASGRP1 p.Pro441Ser (c.1321C>T) is associated with immunodeficiency 64 (ClinVar).

How common is RASGRP1 p.Pro441Ser (c.1321C>T) in the general population?

RASGRP1 p.Pro441Ser (c.1321C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about RASGRP1 p.Pro441Ser (c.1321C>T)?

AlphaMissense predicts likely benign (score 0.0989) — an in-silico prediction, not a clinical call.

RASGRP1 p.Pro441Ser

Q: How is EBV-induced lymphoproliferative disease due to RASGRP1 deficiency inherited?

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

c.1321C>T · rs2542878839 · VCV2500074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 64

Computational evidence

Protein change
AlphaMissense	0.0989	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -5.56	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 63 kb · p 9.6e-13 · regional, not allelic
Overall
CADD	26.3	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 0.00223% East Asian · 1/44,754 alleles

Overall 6.24e-05% 1/1,603,514 alleles · very rare exomes 1/1,451,238 · genomes 0/152,276 · joint denominator

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: RASGRP1
Protein: p.Pro441Ser
Coding: c.1321C>T
MANE Select: NM_005739
dbSNP: rs2542878839
Type: single nucleotide variant
Location: chr15:38505842 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.48 (gnomAD)
Structure: AlphaFold pLDDT 72.43 · 2 PDB
Residue 441: a UniProt-annotated variant site (in imd64; loss of protein expression); a UniProt-annotated variant site (in imd64); a UniProt-annotated variant site (in imd64; no effect on protein expression; decreased t cell activation)

Full RASGRP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 64 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For EBV-induced lymphoproliferative disease due to RASGRP1 deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

RASGRP1 p.Pro441= Likely benign ★ same residue
RASGRP1 c.327-1C>G Pathogenic/Likely pathogenic ★★ same condition
RASGRP1 p.Arg81Ter Pathogenic/Likely pathogenic ★★ same condition
RASGRP1 p.Tyr387His Uncertain significance ★★ ⚠ same condition
RASGRP1 c.676-16G>T Benign/Likely benign ★★ same condition
RASGRP1 p.Asn292= Benign/Likely benign ★★ same condition
RASGRP1 p.Asp143= Benign/Likely benign ★★ same condition
RASGRP1 p.Phe495= Benign ★★ 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/rasgrp1-p-pro441ser (accessed [today's date]).

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