Is BRSK2 p.Pro500= (c.1500G>A) pathogenic?

BRSK2 p.Pro500= (c.1500G>A) is classified Likely benign in BRSK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-01). Rare (popmax 0.512%, mid).

How common is BRSK2 p.Pro500= (c.1500G>A) in the general population?

BRSK2 p.Pro500= (c.1500G>A) is rare (popmax 0.512%, mid) (gnomAD).

BRSK2 p.Pro500=

c.1500G>A · rs3793971 · VCV2641337

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.512%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.005	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.4
Overall
CADD	0.784	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.512% Middle Eastern · 31/6,058 alleles

Filtering AF 0.442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.427%

Overall 0.251% 4,051/1,612,950 alleles · rare exomes 3,787/1,460,596 · genomes 264/152,354 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.72%	139
Middle Easterngrpmax	0.512%	195
South Asian	0.479%	209
East Asian	0.285%	351
Remaining individualsnot grpmax-eligible	0.263%	381
European (non-Finnish)	0.246%	406
Admixed American	0.135%	741
Finnishnot grpmax-eligible	0.111%	900
Amishnot grpmax-eligible	0.11%	912
African / African-American	0.0293%	3,412

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro500=
Coding: c.1500G>A
MANE Select: NM_001256627
dbSNP: rs3793971
Type: single nucleotide variant
Location: chr11:1451375 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.46
Residue 500: the 'disordered' region

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

Similar variants

BRSK2 p.Pro500Ala Uncertain significance ★ ⚠ same residue
BRSK2 p.Pro500Leu Likely benign ★ same residue
BRSK2 p.Arg313Ter Pathogenic/Likely pathogenic ★★ same type
BRSK2 p.Gly28Arg Likely pathogenic ★★ same type
BRSK2 p.Ala68Thr Uncertain significance ★★ ⚠ same type
BRSK2 p.Arg313Gln Uncertain significance ★★ same type
BRSK2 p.Arg65Gln Uncertain significance ★★ ⚠ same type
BRSK2 p.Asp7Asn 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/brsk2-p-pro500 (accessed [today's date]).

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