Is RASGRP2 p.Pro404His (c.1211C>A) pathogenic?

RASGRP2 p.Pro404His (c.1211C>A) is classified Uncertain significance in RASGRP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-16). AlphaMissense: likely benign (0.1141); Very rare (popmax 0.00364%, nfe).

How common is RASGRP2 p.Pro404His (c.1211C>A) in the general population?

RASGRP2 p.Pro404His (c.1211C>A) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about RASGRP2 p.Pro404His (c.1211C>A)?

AlphaMissense predicts likely benign (score 0.1141) — an in-silico prediction, not a clinical call.

RASGRP2 p.Pro404His

c.1211C>A · rs139873299 · VCV2164582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1141	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -8.07	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 1.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 1.3e-07 · regional, not allelic
Overall
CADD	26.2	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 0.00364% European (non-Finnish) · 43/1,179,920 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00285% 46/1,613,858 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00364%	27,440
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00133%	75,044

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: RASGRP2
Protein: p.Pro404His
Coding: c.1211C>A
MANE Select: NM_001098671
dbSNP: rs139873299
Type: single nucleotide variant
Location: chr11:64735627 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 2 PDB
Residue 404: a UniProt-annotated variant site (in bdplt18); a UniProt-annotated variant site (in bdplt18; lack of mutant protein in platelets from a patient homozygous for the mutation); the 'disordered' region

Full RASGRP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RASGRP2 p.Pro404Ser Uncertain significance ★ ⚠ same residue
RASGRP2 p.Pro404= Likely benign ★ same residue
RASGRP2 p.Gly305Asp Likely pathogenic ★★ same type
RASGRP2 p.Arg387Gly Uncertain significance ★★ ⚠ same type
RASGRP2 p.Arg593His Uncertain significance ★★ ⚠ same type
RASGRP2 p.Asn330Lys Uncertain significance ★★ ⚠ same type
RASGRP2 p.Gly331Arg Uncertain significance ★★ ⚠ same type
RASGRP2 p.Gly492Trp 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/rasgrp2-p-pro404his (accessed [today's date]).

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