Is DYRK3 p.Pro520Arg (c.1559C>G) pathogenic?

DYRK3 p.Pro520Arg (c.1559C>G) is classified Uncertain significance in DYRK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely benign (0.2005); Very rare (popmax 0.000339%, nfe).

How common is DYRK3 p.Pro520Arg (c.1559C>G) in the general population?

DYRK3 p.Pro520Arg (c.1559C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about DYRK3 p.Pro520Arg (c.1559C>G)?

AlphaMissense predicts likely benign (score 0.2005) — an in-silico prediction, not a clinical call.

DYRK3 p.Pro520Arg

c.1559C>G · VCV3843108

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2005 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2005	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 13 kb · p 0.23 · regional, not allelic
Overall
CADD	25.1	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 0.000339% European (non-Finnish) · 4/1,179,950 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,820 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)grpmax	0.000339%	294,988

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DYRK3
Protein: p.Pro520Arg
Coding: c.1559C>G
MANE Select: NM_003582
Type: single nucleotide variant
Location: chr1:206648757 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.21 · 1 PDB
Residue 520: the protein kinase domain; a turn

Full DYRK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DYRK3 p.Ala316Ser Uncertain significance ★ ⚠ same type
DYRK3 p.Ala509Ser Uncertain significance ★ ⚠ same type
DYRK3 p.Ala514Gly Uncertain significance ★ ⚠ same type
DYRK3 p.Arg241His Uncertain significance ★ ⚠ same type
DYRK3 p.Arg245His Uncertain significance ★ ⚠ same type
DYRK3 p.Arg248Cys Uncertain significance ★ ⚠ same type
DYRK3 p.Arg255Gln Uncertain significance ★ ⚠ same type
DYRK3 p.Arg255Trp 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/dyrk3-p-pro520arg (accessed [today's date]).

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