Is VRK1 p.Pro67Ser (c.199C>T) pathogenic?

VRK1 p.Pro67Ser (c.199C>T) is classified Uncertain significance in VRK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-25). AlphaMissense: likely benign (0.0845); Very rare (popmax 0.00136%, afr); Associated with Inborn genetic diseases.

What condition is associated with VRK1 p.Pro67Ser (c.199C>T)?

VRK1 p.Pro67Ser (c.199C>T) is associated with Inborn genetic diseases (ClinVar).

How common is VRK1 p.Pro67Ser (c.199C>T) in the general population?

VRK1 p.Pro67Ser (c.199C>T) is very rare (popmax 0.00136%, afr) (gnomAD).

What do computational predictors say about VRK1 p.Pro67Ser (c.199C>T)?

AlphaMissense predicts likely benign (score 0.0845) — an in-silico prediction, not a clinical call.

VRK1 p.Pro67Ser

c.199C>T · VCV3980181

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0845	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -8.23	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 3.3	phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.82 · regional, not allelic
Overall
CADD	20.4	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 0.00136% African / African-American · 1/73,380 alleles

Overall 0.000128% 2/1,557,376 alleles · very rare exomes 2/1,405,378 · genomes 0/151,998 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00136%	73,380
European (non-Finnish)	8.69e-05%	1,151,080

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.Pro67Ser
Coding: c.199C>T
MANE Select: NM_003384
Type: single nucleotide variant
Location: chr14:96837800 (GRCh38)
Gene constraint: LOEUF 0.747 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.37 · 26 PDB
Residue 67: the protein kinase domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VRK1 c.216+1G>C Likely pathogenic ★★ same condition
VRK1 c.889+1G>T Likely pathogenic ★★ same condition
VRK1 p.Arg387His Pathogenic/Likely pathogenic ★★ ⚠ same condition
VRK1 p.Leu155Ter Pathogenic ★★ same condition
VRK1 c.161-3C>T Uncertain significance ★★ same condition
VRK1 p.Ala66Val Uncertain significance ★★ ⚠ same condition
VRK1 p.Arg101His Uncertain significance ★★ ⚠ same condition
VRK1 p.Arg133His Uncertain significance ★★ 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-pro67ser (accessed [today's date]).

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