Is VRK2 p.Arg149Gln (c.446G>A) pathogenic?

VRK2 p.Arg149Gln (c.446G>A) is classified Uncertain significance in VRK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely benign (0.0881); Very rare (popmax 0.00537%, afr).

How common is VRK2 p.Arg149Gln (c.446G>A) in the general population?

VRK2 p.Arg149Gln (c.446G>A) is very rare (popmax 0.00537%, afr) (gnomAD).

What do computational predictors say about VRK2 p.Arg149Gln (c.446G>A)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

VRK2 p.Arg149Gln

c.446G>A · rs768716776 · VCV2211809

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00537%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -6.28	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 12	phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 111 kb · p 1.4e-06 · regional, not allelic
Overall
CADD	25.3	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 0.00537% African / African-American · 4/74,524 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00143%

Overall 0.00212% 34/1,600,596 alleles · very rare exomes 32/1,448,430 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00537%	18,631
European (non-Finnish)	0.00239%	41,764
Admixed American	0.00168%	59,384
South Asian	0.00111%	90,076

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.Arg149Gln
Coding: c.446G>A
MANE Select: NM_006296
dbSNP: rs768716776
Type: single nucleotide variant
Location: chr2:58088442 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.49 · 5 PDB
Residue 149: 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-arg149gln (accessed [today's date]).

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