Is RASGRP1 p.Phe495= (c.1485T>C) pathogenic?

RASGRP1 p.Phe495= (c.1485T>C) is classified Benign in RASGRP1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 26.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency 64.

What condition is associated with RASGRP1 p.Phe495= (c.1485T>C)?

RASGRP1 p.Phe495= (c.1485T>C) is associated with immunodeficiency 64 (ClinVar).

RASGRP1 p.Phe495=

Q: How common is RASGRP1 p.Phe495= (c.1485T>C) in the general population?

RASGRP1 p.Phe495= (c.1485T>C) is common (popmax 26.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1485T>C · rs12324402 · VCV1169965

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 26.3%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

immunodeficiency 64

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 4.6	GERP 1.4, phastCons 1
Overall
CADD	9.591	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 26.3% European (non-Finnish) · 307,903/1,171,424 alleles

Filtering AF 26.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 26.2%

Overall 24.4% 392,172/1,604,328 alleles · common exomes 357,959/1,452,118 · genomes 34,213/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	26.3%	4
Amishnot grpmax-eligible	26.2%	4
Ashkenazi Jewishnot grpmax-eligible	25.7%	4
Remaining individualsnot grpmax-eligible	24.3%	4
Middle Eastern	24.2%	4
South Asian	23.1%	4
Finnishnot grpmax-eligible	22.3%	4
African / African-American	20.1%	5
Admixed American	15.7%	6
East Asian	0.308%	325

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.Phe495=
Coding: c.1485T>C
MANE Select: NM_005739
dbSNP: rs12324402
Type: single nucleotide variant
Location: chr15:38502365 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.48 (gnomAD)
Structure: AlphaFold pLDDT 72.43 · 2 PDB
Residue 495: 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); the ef-hand 1 domain; an α-helix

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 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.Tyr337= Benign/Likely benign ★★ same condition
RASGRP1 c.1720+1G>A 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/rasgrp1-p-phe495 (accessed [today's date]).

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