Is RASGRP2 p.Lys65= (c.195G>A) pathogenic?

RASGRP2 p.Lys65= (c.195G>A) is classified Likely benign in RASGRP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-13). Ultra-rare (popmax 0.0235%, nfe).

How common is RASGRP2 p.Lys65= (c.195G>A) in the general population?

RASGRP2 p.Lys65= (c.195G>A) is ultra-rare (popmax 0.0235%, nfe) (gnomAD).

RASGRP2 p.Lys65=

c.195G>A · rs149463282 · VCV2691520

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0235%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.092	moderately benign-leaning
Splicing
SpliceAI	Δ0.64	acceptor loss · deltas
Pangolin	Δ0.23	gain · loss 0.07 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 2.6	GERP -0.97, phastCons 1
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0235% European (non-Finnish) · 273/1,162,176 alleles

Filtering AF 0.0212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0203%

Overall 0.0195% 309/1,581,090 alleles · ultra-rare exomes 289/1,428,766 · genomes 20/152,324 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0468%	2,136
European (non-Finnish)grpmax	0.0235%	4,257
Remaining individualsnot grpmax-eligible	0.00652%	15,330
African / African-American	0.00268%	37,251
Admixed American	0.00182%	55,086

Finnish 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: RASGRP2
Protein: p.Lys65=
Coding: c.195G>A
MANE Select: NM_001098671
dbSNP: rs149463282
Type: single nucleotide variant
Location: chr11:64741483 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 2 PDB
Residue 65: the n-terminal ras-gef domain; an α-helix

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-lys65 (accessed [today's date]).

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