Is DYRK4 p.Pro127Ser (c.379C>T) pathogenic?

DYRK4 p.Pro127Ser (c.379C>T) is classified Uncertain significance in DYRK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.0705); Rare (popmax 0.139%, afr).

How common is DYRK4 p.Pro127Ser (c.379C>T) in the general population?

DYRK4 p.Pro127Ser (c.379C>T) is rare (popmax 0.139%, afr) (gnomAD).

What do computational predictors say about DYRK4 p.Pro127Ser (c.379C>T)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

DYRK4 p.Pro127Ser

c.379C>T · VCV4245942

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.139%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -5.59	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 -0.49	GERP -2.9
Regional constraint	o/e 0.62	unconstrained · MANE · 2,261 bp · p 0.00035 · regional, not allelic
Overall
CADD	3.104	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P12S vs ClinVar P127S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.139% African / African-American · 104/75,028 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.109%

Overall 0.007% 113/1,614,150 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.139%	721
Admixed American	0.01%	10,004
East Asian	0.00446%	22,441
European (non-Finnish)	8.47e-05%	1,180,020

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: DYRK4
Protein: p.Pro127Ser
Coding: c.379C>T
MANE Select: NM_001394779
Type: single nucleotide variant
Location: chr12:4591214 (GRCh38)
Gene constraint: LOEUF 1.118 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50
Residue 127: the protein kinase domain

Full DYRK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DYRK4 p.Ala153Val Uncertain significance ★ ⚠ same type
DYRK4 p.Ala176Val Uncertain significance ★ ⚠ same type
DYRK4 p.Ala191Gly Uncertain significance ★ ⚠ same type
DYRK4 p.Ala269Thr Uncertain significance ★ ⚠ same type
DYRK4 p.Ala609Val Uncertain significance ★ ⚠ same type
DYRK4 p.Arg255Ser Uncertain significance ★ ⚠ same type
DYRK4 p.Arg291His Uncertain significance ★ ⚠ same type
DYRK4 p.Arg448Thr 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/dyrk4-p-pro127ser (accessed [today's date]).

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