Is BRSK2 p.Pro345= (c.1035G>C) pathogenic?

BRSK2 p.Pro345= (c.1035G>C) is classified Likely benign in BRSK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-21). Ultra-rare (popmax 0.0551%, amr); Associated with BRSK2-related disorder.

What condition is associated with BRSK2 p.Pro345= (c.1035G>C)?

BRSK2 p.Pro345= (c.1035G>C) is associated with BRSK2-related disorder (ClinVar).

How common is BRSK2 p.Pro345= (c.1035G>C) in the general population?

BRSK2 p.Pro345= (c.1035G>C) is ultra-rare (popmax 0.0551%, amr) (gnomAD).

BRSK2 p.Pro345=

c.1035G>C · rs371152368 · VCV3048550

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0551%, amr)

Conditions

BRSK2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.9
Overall
CADD	3.752	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0551% Admixed American · 30/54,492 alleles

Filtering AF 0.0396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0343%

Overall 0.00342% 54/1,580,980 alleles · ultra-rare exomes 26/1,428,744 · genomes 28/152,236 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0551%	1,816
Remaining individualsnot grpmax-eligible	0.0229%	4,371
African / African-American	0.00135%	74,032
European (non-Finnish)	0.000773%	129,314

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.Pro345=
Coding: c.1035G>C
MANE Select: NM_001256627
dbSNP: rs371152368
Type: single nucleotide variant
Location: chr11:1445628 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.46
Residue 345: the 'disordered' region

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

Disease context

BRSK2-related disorder

Similar variants

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
BRSK2 p.Asp198Glu 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-pro345 (accessed [today's date]).

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