Is STIM1 p.Pro596Ser (c.1786C>T) pathogenic?

STIM1 p.Pro596Ser (c.1786C>T) is classified Uncertain significance in STIM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely benign (0.0686); Very rare (popmax 8.47e-05%, nfe); Associated with Stormorken syndrome.

What condition is associated with STIM1 p.Pro596Ser (c.1786C>T)?

STIM1 p.Pro596Ser (c.1786C>T) is associated with Stormorken syndrome, tubular aggregate myopathy, combined immunodeficiency due to STIM1 deficiency (ClinVar).

How common is STIM1 p.Pro596Ser (c.1786C>T) in the general population?

STIM1 p.Pro596Ser (c.1786C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Stormorken-Sjaastad-Langslet syndrome inherited?

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

What do computational predictors say about STIM1 p.Pro596Ser (c.1786C>T)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

STIM1 p.Pro596Ser

c.1786C>T · VCV3754991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Stormorken syndrome

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -5.73	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 2.3	GERP 1.6, phastCons 0.74
Regional constraint	o/e 0.95	unconstrained · MANE · 8,451 bp · p 0.35 · regional, not allelic
Overall
CADD	16.16	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 P565S vs ClinVar P596S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.2e-05% 1/1,614,200 alleles · very rare exomes 1/1,461,880 · genomes 0/152,320 · 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: STIM1
Protein: p.Pro596Ser
Coding: c.1786C>T
MANE Select: NM_001382567
Type: single nucleotide variant
Location: chr11:4091433 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 6 PDB

Full STIM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Stormorken syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tubular aggregate myopathy combined immunodeficiency due to STIM1 deficiency

For Stormorken-Sjaastad-Langslet syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

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STIM1 p.Arg50Ter Pathogenic/Likely pathogenic ★★ same condition
STIM1 p.His109Arg Pathogenic/Likely pathogenic ★★ same condition
STIM1 p.Ser88Gly Pathogenic/Likely pathogenic ★★ same condition
STIM1 c.792-3C>A Uncertain significance ★★ same condition
STIM1 c.792-3C>G Uncertain significance ★★ same condition
STIM1 p.Ala163Asp Uncertain significance ★★ ⚠ same condition
STIM1 p.Ala31Pro 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/stim1-p-pro596ser (accessed [today's date]).

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