Is RASGRP1 p.Pro746= (c.2238T>C) pathogenic?

RASGRP1 p.Pro746= (c.2238T>C) is classified Likely benign in RASGRP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). Very rare (popmax 0.000932%, nfe).

How common is RASGRP1 p.Pro746= (c.2238T>C) in the general population?

RASGRP1 p.Pro746= (c.2238T>C) is very rare (popmax 0.000932%, nfe) (gnomAD).

RASGRP1 p.Pro746=

c.2238T>C · rs1293689865 · VCV1929632

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

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 -1.4	GERP -4.4
Overall
CADD	10.73	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,179,894 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000744% 12/1,613,854 alleles · very rare exomes 9/1,461,638 · genomes 3/152,216 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
European (non-Finnish)grpmax	0.000932%	107,263

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro746=
Coding: c.2238T>C
MANE Select: NM_005739
dbSNP: rs1293689865
Type: single nucleotide variant
Location: chr15:38494403 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.48 (gnomAD)
Structure: AlphaFold pLDDT 72.43 · 2 PDB
Residue 746: the 'pt region; mediates the bcr-dependent translocation to plasma membrane' region; 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

Similar variants

RASGRP1 c.327-1C>G Pathogenic/Likely pathogenic ★★ same type
RASGRP1 p.Arg81Ter Pathogenic/Likely pathogenic ★★ same type
RASGRP1 p.Ala57Ser Uncertain significance ★★ ⚠ same type
RASGRP1 p.Arg167Cys Uncertain significance ★★ ⚠ same type
RASGRP1 p.Arg177His Uncertain significance ★★ ⚠ same type
RASGRP1 p.Arg663Gln Uncertain significance ★★ ⚠ same type
RASGRP1 p.Arg741His Uncertain significance ★★ ⚠ same type
RASGRP1 p.Asn241Ser Uncertain significance ★★ ⚠ same type

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-pro746 (accessed [today's date]).

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