Is VRK1 p.Pro2fs (c.3dup) pathogenic?

VRK1 p.Pro2fs (c.3dup) is classified Likely pathogenic in VRK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-07). Very rare (popmax 0.000254%, nfe); Associated with pontocerebellar hypoplasia type 1A.

What condition is associated with VRK1 p.Pro2fs (c.3dup)?

VRK1 p.Pro2fs (c.3dup) is associated with pontocerebellar hypoplasia type 1A, neuronopathy, distal hereditary motor, autosomal recessive 10 (ClinVar).

How common is VRK1 p.Pro2fs (c.3dup) in the general population?

VRK1 p.Pro2fs (c.3dup) is very rare (popmax 0.000254%, nfe) (gnomAD).

VRK1 p.Pro2fs

c.3dup · VCV3576914

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

pontocerebellar hypoplasia type 1A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 2.8, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,620 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,164 alleles · very rare

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: VRK1
Protein: p.Pro2fs
Coding: c.3dup
MANE Select: NM_003384
Type: Duplication
Location: chr14:96833473 (GRCh38)
Gene constraint: LOEUF 0.747 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.37 · 26 PDB
Residue 2: a turn

Full VRK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pontocerebellar hypoplasia type 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronopathy, distal hereditary motor, autosomal recessive 10

Similar variants

VRK1 p.Glu382fs Pathogenic/Likely pathogenic ★★ same condition
VRK1 p.Cys289fs Likely pathogenic ★ same condition
VRK1 p.Gln12fs Pathogenic ★ same condition
VRK1 p.Glu318fs Pathogenic ★ same condition
VRK1 p.Ile130fs Pathogenic ★ same condition
VRK1 p.Thr305fs Pathogenic ★ same condition
VRK1 p.Thr355fs Pathogenic ★ same condition
VRK1 p.Tyr113Ter Pathogenic ★ 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/vrk1-p-pro2fs (accessed [today's date]).

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