Is CSPP1 p.Glu755fs (c.2259_2260del) pathogenic?

CSPP1 p.Glu755fs (c.22592260del) is classified Pathogenic in CSPP1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-06-04). Ultra-rare (popmax 0.0136%, afr); Associated with CSPP1-related disorder.

What condition is associated with CSPP1 p.Glu755fs (c.2259_2260del)?

CSPP1 p.Glu755fs (c.2259_2260del) is associated with CSPP1-related disorder, Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Glu755fs (c.2259_2260del) in the general population?

CSPP1 p.Glu755fs (c.2259_2260del) is ultra-rare (popmax 0.0136%, afr) (gnomAD).

CSPP1 p.Glu755fs

c.2259_2260del · rs587777139 · VCV100667

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, afr)

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 20 of 31
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Overall
CADD	29.9	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 0.0136% African / African-American · 10/73,720 alleles

Filtering AF 0.00831% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00778%

Overall 0.00926% 148/1,597,440 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0136%	7,372
East Asian	0.0135%	7,423
South Asian	0.0103%	9,702
European (non-Finnish)	0.0098%	10,201
Remaining individualsnot grpmax-eligible	0.00648%	15,424
Admixed American	0.00348%	28,725
Finnishnot grpmax-eligible	0.00314%	31,812

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.Glu755fs
Coding: c.2259_2260del
MANE Select: NM_001382391
dbSNP: rs587777139
Type: Deletion
Location: chr8:67158463 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 57.34
Residue 755: the 'disordered' region

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 p.Glu755Lys Uncertain significance ★ same residue
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.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-glu755fs (accessed [today's date]).

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