Is CSPP1 p.Lys819fs (c.2456_2459del) pathogenic?

CSPP1 p.Lys819fs (c.24562459del) is classified Pathogenic in CSPP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-05). Very rare (popmax 0.00662%, sas); Associated with Joubert syndrome 21.

What condition is associated with CSPP1 p.Lys819fs (c.2456_2459del)?

CSPP1 p.Lys819fs (c.2456_2459del) is associated with Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Lys819fs (c.2456_2459del) in the general population?

CSPP1 p.Lys819fs (c.2456_2459del) is very rare (popmax 0.00662%, sas) (gnomAD).

CSPP1 p.Lys819fs

c.2456_2459del · rs761382780 · VCV217650

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00662%, sas)

Conditions

Joubert syndrome 21

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 21 of 31
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4	GERP 0.83, phastCons 1
Region caveats
Repeat context	tandem	(GAAGAAA)n simple repeat · ambiguous alignment · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00662% South Asian · 6/90,648 alleles

Filtering AF 0.00287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00196%

Overall 0.00048% 7/1,459,410 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00662%	15,108
European (non-Finnish)	8.48e-05%	1,178,555

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.Lys819fs
Coding: c.2456_2459del
MANE Select: NM_001382391
dbSNP: rs761382780
Type: Microsatellite
Location: chr8:67159047 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 57.34
Residue 819: the 'disordered' region

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

Disease context

Joubert syndrome 21 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CSPP1 p.Glu822fs Pathogenic/Likely pathogenic ★★ same condition
CSPP1 c.2392-8_2392-4del Benign/Likely benign ★★ same condition
CSPP1 p.Arg761fs Pathogenic ★ same condition
CSPP1 p.Asn515fs Pathogenic ★ same condition
CSPP1 p.Glu204delinsIleTer Pathogenic ★ same condition
CSPP1 p.Glu824fs Pathogenic ★ same condition
CSPP1 p.Lys619fs Pathogenic ★ same condition
CSPP1 p.Lys791fs 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-lys819fs (accessed [today's date]).

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