Is VRK2 p.Asp232Glu (c.696C>G) pathogenic?

VRK2 p.Asp232Glu (c.696C>G) is classified Uncertain significance in VRK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.96); Very rare (popmax 0.00661%, nfe).

How common is VRK2 p.Asp232Glu (c.696C>G) in the general population?

VRK2 p.Asp232Glu (c.696C>G) is very rare (popmax 0.00661%, nfe) (gnomAD).

What do computational predictors say about VRK2 p.Asp232Glu (c.696C>G)?

AlphaMissense predicts likely pathogenic (score 0.96) — an in-silico prediction, not a clinical call.

VRK2 p.Asp232Glu

c.696C>G · rs777534671 · VCV2356164

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.96 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00661%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.96	likely pathogenic · top 5% in VRK2
REVEL	0.712	pathogenic-leaning
SaProt	LLR -10.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.29	acceptor loss, 19 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.16	GERP -0.053, phastCons 0.041
Regional constraint	o/e 1.20	unconstrained · MANE · 111 kb · p 1.4e-06 · regional, not allelic
Overall
CADD	19.37	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00661% European (non-Finnish) · 78/1,179,538 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00502% 81/1,612,836 alleles · very rare exomes 78/1,460,704 · genomes 3/152,132 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00661%	15,122
African / African-American	0.00267%	37,415
Remaining individualsnot grpmax-eligible	0.0016%	62,444

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: VRK2
Protein: p.Asp232Glu
Coding: c.696C>G
MANE Select: NM_006296
dbSNP: rs777534671
Type: single nucleotide variant
Location: chr2:58131827 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.49 · 5 PDB
Residue 232: the protein kinase domain; an α-helix

Full VRK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

VRK2 p.Asp435Asn Uncertain significance ★★ ⚠ same type
FANCL c.*95A>G Benign/Likely benign ★★ same type
FANCL c.1093-11T>A Conflicting classifications of pathogenicity ★ same type
FANCL c.*128G>A Uncertain significance ★ ⚠ same type
FANCL c.*165A>C Uncertain significance ★ same type
FANCL c.*281C>G Uncertain significance ★ ⚠ same type
FANCL c.*434A>G Uncertain significance ★ same type
FANCL c.*515A>C 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/vrk2-p-asp232glu (accessed [today's date]).

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