Is RAPGEF2 p.Pro1641= (c.4923C>T) pathogenic?

RAPGEF2 p.Pro1641= (c.4923C>T) is classified Benign in RAPGEF2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-11-07). Common (popmax 59.5%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with epilepsy, familial adult myoclonic, 7.

What condition is associated with RAPGEF2 p.Pro1641= (c.4923C>T)?

RAPGEF2 p.Pro1641= (c.4923C>T) is associated with epilepsy, familial adult myoclonic, 7 (ClinVar).

RAPGEF2 p.Pro1641=

Q: How common is RAPGEF2 p.Pro1641= (c.4923C>T) in the general population?

RAPGEF2 p.Pro1641= (c.4923C>T) is common (popmax 59.5%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4923C>T · rs1135004 · VCV1327941

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 59.5%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

epilepsy, familial adult myoclonic, 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.48	GERP -3.4, phastCons 0.014
Overall
CADD	4.915	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 59.5% European (non-Finnish) · 701,441/1,179,786 alleles

Filtering AF 59.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 59.3%

Overall 54.4% 877,690/1,613,652 alleles · common exomes 807,230/1,461,586 · genomes 70,460/152,066 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	62.7%	2
European (non-Finnish)grpmax	59.5%	2
Finnishnot grpmax-eligible	53.3%	2
Admixed American	52.7%	2
Remaining individualsnot grpmax-eligible	51%	2
Middle Eastern	47.4%	2
Ashkenazi Jewishnot grpmax-eligible	45.8%	2
South Asian	42.2%	2
African / African-American	26.3%	4
East Asian	7.83%	13

Amish 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: RAPGEF2
Protein: p.Pro1641=
Coding: c.4923C>T
MANE Select: NM_001394067
dbSNP: rs1135004
Type: single nucleotide variant
Location: chr4:159356124 (GRCh38)
Gene constraint: LOEUF 0.371 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.40 · 1 PDB

Full RAPGEF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epilepsy, familial adult myoclonic, 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RAPGEF2 c.282-12C>A Benign ★★ same condition
RAPGEF2 c.4958-8A>G Uncertain significance ★ same condition
RAPGEF2 p.Ala1659Thr Uncertain significance ★ ⚠ same condition
RAPGEF2 p.Cys962Tyr Uncertain significance ★ ⚠ same condition
RAPGEF2 p.Glu273Asp Uncertain significance ★ ⚠ same condition
RAPGEF2 p.Gly587= Uncertain significance ★ same condition
RAPGEF2 c.1303-68TG[16] Benign ★ same condition
RAPGEF2 c.1303-68TG[17] Benign ★ 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/rapgef2-p-pro1641 (accessed [today's date]).

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