Is STK4 p.Pro223Arg (c.668C>G) pathogenic?

STK4 p.Pro223Arg (c.668C>G) is classified Uncertain significance in STK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-02). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with STK4 p.Pro223Arg (c.668C>G)?

STK4 p.Pro223Arg (c.668C>G) is associated with Inborn genetic diseases (ClinVar).

How common is STK4 p.Pro223Arg (c.668C>G) in the general population?

STK4 p.Pro223Arg (c.668C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STK4 p.Pro223Arg (c.668C>G)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

STK4 p.Pro223Arg

c.668C>G · VCV3450727

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic
REVEL	0.689	pathogenic-leaning
SaProt	LLR -16.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 31 kb · p 4.8e-09 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: STK4
Protein: p.Pro223Arg
Coding: c.668C>G
MANE Select: NM_006282
Type: single nucleotide variant
Location: chr20:44995232 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 76.45 · 16 PDB
Residue 223: the protein kinase domain; a turn

Full STK4 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

STK4 p.Ala391Val Uncertain significance ★★ ⚠ same condition
STK4 p.Ala479Ser Uncertain significance ★★ ⚠ same condition
STK4 p.Arg310Gln Uncertain significance ★★ ⚠ same condition
STK4 p.Arg483Trp Uncertain significance ★★ ⚠ same condition
STK4 p.Asp124Asn Uncertain significance ★★ ⚠ same condition
STK4 p.Asp358Asn Uncertain significance ★★ ⚠ same condition
STK4 p.Gln314Pro Uncertain significance ★★ ⚠ same condition
STK4 p.Glu434Lys 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/stk4-p-pro223arg (accessed [today's date]).

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