Is STK33 p.Ser504Pro (c.1510T>C) pathogenic?

STK33 p.Ser504Pro (c.1510T>C) is classified Uncertain significance in STK33 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely benign (0.0695); Ultra-rare (popmax 0.0867%, amr).

How common is STK33 p.Ser504Pro (c.1510T>C) in the general population?

STK33 p.Ser504Pro (c.1510T>C) is ultra-rare (popmax 0.0867%, amr) (gnomAD).

What do computational predictors say about STK33 p.Ser504Pro (c.1510T>C)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

STK33 p.Ser504Pro

c.1510T>C · VCV4176758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0867%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -6.93	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 -0.23	GERP -4.8, phastCons 0.001
Regional constraint	o/e 1.04	unconstrained · MANE · 82 kb · p 0.29 · regional, not allelic
Overall
CADD	7.052	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 0.0867% Admixed American · 52/59,974 alleles

Filtering AF 0.0679% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0611%

Overall 0.00322% 52/1,614,038 alleles · ultra-rare exomes 48/1,461,894 · genomes 4/152,144 · joint denominator

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: STK33
Protein: p.Ser504Pro
Coding: c.1510T>C
MANE Select: NM_001352389
Type: single nucleotide variant
Location: chr11:8392545 (GRCh38)
Gene constraint: LOEUF 1.011 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.88 · 1 PDB
Residue 504: a UniProt-annotated variant site (in spgf93; uncertain significance); the 'disordered' region

Full STK33 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

STK33 p.Ala223Ser Uncertain significance ★ ⚠ same type
STK33 p.Ala223Thr Uncertain significance ★ ⚠ same type
STK33 p.Ala269Val Uncertain significance ★ ⚠ same type
STK33 p.Ala372Thr Uncertain significance ★ same type
STK33 p.Ala506Thr Uncertain significance ★ ⚠ same type
STK33 p.Arg120Gly Uncertain significance ★ ⚠ same type
STK33 p.Arg206Lys Uncertain significance ★ ⚠ same type
STK33 p.Arg318His 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/stk33-p-ser504pro (accessed [today's date]).

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