Is DYRK2 p.Ser474Phe (c.1421C>T) pathogenic?

DYRK2 p.Ser474Phe (c.1421C>T) is classified Uncertain significance in DYRK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.4029); Absent from gnomAD v4.1.

How common is DYRK2 p.Ser474Phe (c.1421C>T) in the general population?

DYRK2 p.Ser474Phe (c.1421C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYRK2 p.Ser474Phe (c.1421C>T)?

AlphaMissense predicts ambiguous (score 0.4029) — an in-silico prediction, not a clinical call.

DYRK2 p.Ser474Phe

c.1421C>T · VCV4245931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4029 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4029	ambiguous
REVEL	0.133	moderately benign-leaning
SaProt	LLR -12.38	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	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	26.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYRK2
Protein: p.Ser474Phe
Coding: c.1421C>T
MANE Select: NM_006482
Type: single nucleotide variant
Location: chr12:67658328 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 77.04 · 26 PDB
Residue 474: the protein kinase domain

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

Similar variants

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
DYRK2 p.Arg274Trp 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-ser474phe (accessed [today's date]).

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