Is DYRK2 p.Pro533Ser (c.1597C>T) pathogenic?

DYRK2 p.Pro533Ser (c.1597C>T) is classified Uncertain significance in DYRK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.095); Ultra-rare (popmax 0.0661%, mid).

How common is DYRK2 p.Pro533Ser (c.1597C>T) in the general population?

DYRK2 p.Pro533Ser (c.1597C>T) is ultra-rare (popmax 0.0661%, mid) (gnomAD).

What do computational predictors say about DYRK2 p.Pro533Ser (c.1597C>T)?

AlphaMissense predicts likely benign (score 0.095) — an in-silico prediction, not a clinical call.

DYRK2 p.Pro533Ser

c.1597C>T · rs936839760 · VCV3086608

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.095 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.095	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -8.98	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 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 1,203 bp · p 3.1e-08 · regional, not allelic
Overall
CADD	21.0	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 0.0661% Middle Eastern · 4/6,054 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00285% 46/1,611,394 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0661%	1,514
Remaining individualsnot grpmax-eligible	0.0208%	4,797
African / African-American	0.0107%	9,361
South Asian	0.00221%	45,255
European (non-Finnish)	0.00161%	62,037

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: DYRK2
Protein: p.Pro533Ser
Coding: c.1597C>T
MANE Select: NM_006482
dbSNP: rs936839760
Type: single nucleotide variant
Location: chr12:67658504 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 77.04 · 26 PDB
Residue 533: the protein kinase domain; an α-helix

Full DYRK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DYRK2 p.Pro533Thr Uncertain significance ★ ⚠ same residue
DYRK2 p.Ala413Gly Uncertain significance ★ ⚠ same type
DYRK2 p.Ala499Thr Uncertain significance ★ ⚠ same type
DYRK2 p.Ala499Val Uncertain significance ★ ⚠ same type
DYRK2 p.Ala581Val Uncertain significance ★ ⚠ same type
DYRK2 p.Ala9Val Uncertain significance ★ ⚠ same type
DYRK2 p.Arg125Gln Uncertain significance ★ ⚠ same type
DYRK2 p.Arg268Gln 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/dyrk2-p-pro533ser (accessed [today's date]).

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