Is BRSK2 p.Pro586= (c.1758G>A) pathogenic?

BRSK2 p.Pro586= (c.1758G>A) is classified Likely benign in BRSK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-12-02). Ultra-rare (popmax 0.054%, nfe); Associated with BRSK2-related disorder.

What condition is associated with BRSK2 p.Pro586= (c.1758G>A)?

BRSK2 p.Pro586= (c.1758G>A) is associated with BRSK2-related disorder (ClinVar).

How common is BRSK2 p.Pro586= (c.1758G>A) in the general population?

BRSK2 p.Pro586= (c.1758G>A) is ultra-rare (popmax 0.054%, nfe) (gnomAD).

BRSK2 p.Pro586=

c.1758G>A · rs370973176 · VCV3035082

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.054%, nfe)

Conditions

BRSK2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.014	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20
Overall
CADD	0.142	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.054% European (non-Finnish) · 632/1,170,982 alleles

Filtering AF 0.0505% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.049%

Overall 0.0443% 705/1,593,026 alleles · ultra-rare exomes 679/1,440,892 · genomes 26/152,134 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.054%	1,853
Remaining individualsnot grpmax-eligible	0.052%	1,925
East Asian	0.0246%	4,065
Admixed American	0.0213%	4,690
Middle Eastern	0.0167%	5,974
African / African-American	0.0135%	7,414
Finnishnot grpmax-eligible	0.0112%	8,924

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: BRSK2
Protein: p.Pro586=
Coding: c.1758G>A
MANE Select: NM_001256627
dbSNP: rs370973176
Type: single nucleotide variant
Location: chr11:1456437 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.46

Full BRSK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

BRSK2-related disorder

Similar variants

BRSK2 p.Pro586Ser Uncertain significance ★ ⚠ same residue
BRSK2 p.Arg313Ter Pathogenic/Likely pathogenic ★★ same condition
BRSK2 p.Cys39Ter Pathogenic ★ same condition
BRSK2 c.91+21048C>T Uncertain significance ★ same condition
BRSK2 c.91+21210C>T Uncertain significance ★ same condition
BRSK2 c.92-5C>A Uncertain significance ★ same condition
BRSK2 c.*255C>T Uncertain significance ★ same condition
BRSK2 p.Ala697Val 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/brsk2-p-pro586 (accessed [today's date]).

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