Is STK4 p.Pro241Ser (c.721C>T) pathogenic?

STK4 p.Pro241Ser (c.721C>T) is classified Uncertain significance in STK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-15). AlphaMissense: likely pathogenic (0.58); Ultra-rare (popmax 0.0227%, afr); Associated with combined immunodeficiency due to STK4 deficiency.

What condition is associated with STK4 p.Pro241Ser (c.721C>T)?

STK4 p.Pro241Ser (c.721C>T) is associated with combined immunodeficiency due to STK4 deficiency (ClinVar).

How common is STK4 p.Pro241Ser (c.721C>T) in the general population?

STK4 p.Pro241Ser (c.721C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about STK4 p.Pro241Ser (c.721C>T)?

AlphaMissense predicts likely pathogenic (score 0.58) — an in-silico prediction, not a clinical call.

STK4 p.Pro241Ser

Q: How is Combined immunodeficiency due to STK4 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.721C>T · rs371236375 · VCV540523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.58 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency due to STK4 deficiency

Computational evidence

Protein change
AlphaMissense	0.58	likely pathogenic
REVEL	0.287	benign-leaning
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 78 kb · p 0.062 · regional, not allelic
Overall
CADD	27.9	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

Grpmax group 0.0227% African / African-American · 17/75,018 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0013% 21/1,613,990 alleles · ultra-rare exomes 11/1,461,688 · genomes 10/152,302 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,413
Remaining individualsnot grpmax-eligible	0.0032%	31,252
South Asian	0.0022%	45,536

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: STK4
Protein: p.Pro241Ser
Coding: c.721C>T
MANE Select: NM_006282
dbSNP: rs371236375
Type: single nucleotide variant
Location: chr20:44997196 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 76.45 · 16 PDB
Residue 241: the protein kinase domain; an α-helix

Full STK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined immunodeficiency due to STK4 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to STK4 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

STK4 p.Pro241Leu Uncertain significance ★ ⚠ same residue
STK4 p.Arg115Ter Pathogenic/Likely pathogenic ★★ same condition
STK4 p.Arg117Ter Pathogenic ★★ same condition
STK4 p.Arg148Ter Pathogenic ★★ same condition
STK4 p.Arg245Ter Pathogenic/Likely pathogenic ★★ same condition
STK4 p.Ala391Val Uncertain significance ★★ ⚠ same condition
STK4 p.Ala479Ser Uncertain significance ★★ ⚠ same condition
STK4 p.Arg310Gln 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-pro241ser (accessed [today's date]).

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