Is RASGRP2 p.Ser489Cys (c.1466C>G) pathogenic?

RASGRP2 p.Ser489Cys (c.1466C>G) is classified Likely benign in RASGRP2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.0986); Rare (popmax 0.404%, amr).

How common is RASGRP2 p.Ser489Cys (c.1466C>G) in the general population?

RASGRP2 p.Ser489Cys (c.1466C>G) is rare (popmax 0.404%, amr) (gnomAD).

What do computational predictors say about RASGRP2 p.Ser489Cys (c.1466C>G)?

AlphaMissense predicts likely benign (score 0.0986) — an in-silico prediction, not a clinical call.

RASGRP2 p.Ser489Cys

c.1466C>G · rs140514685 · VCV501656

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0986 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.404%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0986	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -8.85	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 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 1.3e-07 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.404% Admixed American · 206/51,014 alleles

Filtering AF 0.359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.35%

Overall 0.297% 4,613/1,551,578 alleles · rare exomes 4,245/1,399,234 · genomes 368/152,344 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.404%	248
European (non-Finnish)	0.363%	276
Remaining individualsnot grpmax-eligible	0.271%	369
Middle Eastern	0.169%	592
Ashkenazi Jewishnot grpmax-eligible	0.105%	955
African / African-American	0.0506%	1,978
Finnishnot grpmax-eligible	0.01%	9,963

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.Ser489Cys
Coding: c.1466C>G
MANE Select: NM_001098671
dbSNP: rs140514685
Type: single nucleotide variant
Location: chr11:64730141 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 2 PDB
Residue 489: 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

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

Similar variants

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
RASGRP2 p.Leu107Ile Uncertain significance ★★ ⚠ same type
RASGRP2 p.Lys55Met 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-ser489cys (accessed [today's date]).

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