Is BRSK2 p.Lys681fs (c.2042del) pathogenic?

BRSK2 p.Lys681fs (c.2042del) is classified Uncertain significance in BRSK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-24). Very rare (popmax 0.002%, amr).

How common is BRSK2 p.Lys681fs (c.2042del) in the general population?

BRSK2 p.Lys681fs (c.2042del) is very rare (popmax 0.002%, amr) (gnomAD).

BRSK2 p.Lys681fs

c.2042del · rs1847343158 · VCV871726

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.002%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (20 of 20) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.6	phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.002% Admixed American · 1/50,002 alleles

Filtering AF 0.00079% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000626%

Overall 0.00105% 16/1,522,330 alleles · very rare exomes 15/1,374,676 · genomes 1/147,654 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.002%	50,002
European (non-Finnish)	0.00132%	76,032

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.Lys681fs
Coding: c.2042del
MANE Select: NM_001256627
dbSNP: rs1847343158
Type: Deletion
Location: chr11:1460553 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.46
Residue 681: the 'disordered' region

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

Similar variants

BRSK2 c.1940-3_1940-2del Likely pathogenic ★ same type
BRSK2 c.1987+2del Likely pathogenic ★ same type
BRSK2 p.Asn524fs Likely pathogenic ★ same type
BRSK2 p.Asp540fs Pathogenic ★ same type
BRSK2 p.Lys44fs Likely pathogenic ★ same type
BRSK2 p.Ser467fs Likely pathogenic ★ same type
BRSK2 p.Val473fs Pathogenic ★ same type
BRSK2 c.186+5_186+50del Conflicting classifications of pathogenicity ★ 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-lys681fs (accessed [today's date]).

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