Is RASGRP2 p.Arg486His (c.1457G>A) pathogenic?

RASGRP2 p.Arg486His (c.1457G>A) is classified Uncertain significance in RASGRP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). AlphaMissense: likely benign (0.0768); Ultra-rare (popmax 0.0309%, sas); Associated with Inborn genetic diseases.

What condition is associated with RASGRP2 p.Arg486His (c.1457G>A)?

RASGRP2 p.Arg486His (c.1457G>A) is associated with Inborn genetic diseases (ClinVar).

How common is RASGRP2 p.Arg486His (c.1457G>A) in the general population?

RASGRP2 p.Arg486His (c.1457G>A) is ultra-rare (popmax 0.0309%, sas) (gnomAD).

What do computational predictors say about RASGRP2 p.Arg486His (c.1457G>A)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

RASGRP2 p.Arg486His

c.1457G>A · rs760132708 · VCV2309926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0309%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -7.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 0.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 1.3e-07 · regional, not allelic
Overall
CADD	24.6	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 0.0309% South Asian · 26/84,064 alleles

Filtering AF 0.0217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0185%

Overall 0.00193% 30/1,551,606 alleles · ultra-rare exomes 28/1,399,282 · genomes 2/152,324 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0309%	3,233
East Asian	0.00244%	40,912
European (non-Finnish)	0.000262%	382,338

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.Arg486His
Coding: c.1457G>A
MANE Select: NM_001098671
dbSNP: rs760132708
Type: single nucleotide variant
Location: chr11:64730150 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 2 PDB
Residue 486: 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 ef-hand 2 domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RASGRP2 p.Arg593His Uncertain significance ★★ ⚠ same condition
RASGRP2 p.Gly492Trp Uncertain significance ★★ ⚠ same condition
RASGRP2 p.Lys55Met Uncertain significance ★★ same condition
RASGRP2 p.Thr396Met Uncertain significance ★★ ⚠ same condition
RASGRP2 p.Ala414Thr Uncertain significance ★ ⚠ same condition
RASGRP2 p.Ala517Ser Uncertain significance ★ ⚠ same condition
RASGRP2 p.Arg113Gln Uncertain significance ★ ⚠ same condition
RASGRP2 p.Arg131Gln Uncertain significance ★ ⚠ 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/rasgrp2-p-arg486his (accessed [today's date]).

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