Is CSPP1 p.Lys596fs (c.1787_1790del) pathogenic?

CSPP1 p.Lys596fs (c.17871790del) is classified Pathogenic/Likely pathogenic in CSPP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-16). Very rare (popmax 0.0033%, sas); Associated with CSPP1-related disorder.

What condition is associated with CSPP1 p.Lys596fs (c.1787_1790del)?

CSPP1 p.Lys596fs (c.1787_1790del) is associated with CSPP1-related disorder, Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Lys596fs (c.1787_1790del) in the general population?

CSPP1 p.Lys596fs (c.1787_1790del) is very rare (popmax 0.0033%, sas) (gnomAD).

CSPP1 p.Lys596fs

c.1787_1790del · rs1409618249 · VCV1451541

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Conditions

CSPP1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 31
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 2, phastCons 1
Overall
CADD	28.6	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 0.0033% South Asian · 3/91,000 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000434% 7/1,613,602 alleles · very rare exomes 6/1,461,438 · genomes 1/152,164 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,333
African / African-American	0.00134%	74,886
European (non-Finnish)	0.000254%	393,278

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: CSPP1
Protein: p.Lys596fs
Coding: c.1787_1790del
MANE Select: NM_001382391
dbSNP: rs1409618249
Type: Deletion
Location: chr8:67132038 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 57.34

Full CSPP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CSPP1-related disorder

Also linked: Joubert syndrome 21

Similar variants

CSPP1 c.-54_-51del Likely pathogenic ★★ same condition
CSPP1 p.Asn908fs Pathogenic ★★ same condition
CSPP1 p.Gln753fs Pathogenic/Likely pathogenic ★★ same condition
CSPP1 p.Glu11fs Pathogenic/Likely pathogenic ★★ same condition
CSPP1 p.Glu755fs Pathogenic ★★ same condition
CSPP1 p.Glu89fs Pathogenic ★★ same condition
CSPP1 p.His85fs Pathogenic ★★ same condition
CSPP1 p.Ile841fs Pathogenic/Likely pathogenic ★★ 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/cspp1-p-lys596fs (accessed [today's date]).

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