Is CSPP1 p.Ile454fs (c.1360dup) pathogenic?

CSPP1 p.Ile454fs (c.1360dup) is classified Pathogenic in CSPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). Very rare (popmax 0.000763%, nfe); Associated with Joubert syndrome 21.

What condition is associated with CSPP1 p.Ile454fs (c.1360dup)?

CSPP1 p.Ile454fs (c.1360dup) is associated with Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Ile454fs (c.1360dup) in the general population?

CSPP1 p.Ile454fs (c.1360dup) is very rare (popmax 0.000763%, nfe) (gnomAD).

CSPP1 p.Ile454fs

c.1360dup · VCV4699335

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

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 13 of 31
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.5	GERP 0.85, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,942 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000616% 9/1,461,790 alleles · very rare

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.Ile454fs
Coding: c.1360dup
MANE Select: NM_001382391
Type: Duplication
Location: chr8:67115984 (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

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

Similar variants

CSPP1 p.Glu843fs Pathogenic/Likely pathogenic ★★ same condition
CSPP1 p.Lys45Ter Pathogenic ★★ same condition
CSPP1 p.Tyr273Ter Pathogenic ★★ same condition
CSPP1 c.1023-7dup Benign/Likely benign ★★ same condition
CSPP1 c.1288-12dup Benign/Likely benign ★★ same condition
CSPP1 c.200-5dup Benign/Likely benign ★★ same condition
CSPP1 c.-10-5dup Benign/Likely benign ★★ same condition
CSPP1 p.Ile48fs 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-ile454fs (accessed [today's date]).

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