Is CSPP1 p.Ile841fs (c.2521_2524del) pathogenic?

CSPP1 p.Ile841fs (c.25212524del) is classified Pathogenic/Likely pathogenic in CSPP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-30). Very rare (popmax 0.00323%, nfe); Associated with CSPP1-related disorder.

What condition is associated with CSPP1 p.Ile841fs (c.2521_2524del)?

CSPP1 p.Ile841fs (c.2521_2524del) is associated with CSPP1-related disorder, Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Ile841fs (c.2521_2524del) in the general population?

CSPP1 p.Ile841fs (c.2521_2524del) is very rare (popmax 0.00323%, nfe) (gnomAD).

CSPP1 p.Ile841fs

c.2521_2524del · rs755739341 · VCV1031405

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00323%, nfe)

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 21 of 31
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.88	GERP -0.26, phastCons 0.66
Overall
CADD	21.5	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 0.00323% European (non-Finnish) · 38/1,176,424 alleles

Filtering AF 0.0024% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00263% 42/1,599,630 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00324%	30,910
European (non-Finnish)grpmax	0.00323%	30,959
African / African-American	0.00136%	73,718
South Asian	0.00115%	87,070

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile841fs
Coding: c.2521_2524del
MANE Select: NM_001382391
dbSNP: rs755739341
Type: Deletion
Location: chr8:67159117 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 57.34
Residue 841: 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.Ile841Thr Conflicting classifications of pathogenicity ★ same residue
CSPP1 p.Ile841= Likely benign ★ 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.Glu755fs Pathogenic ★★ same condition
CSPP1 p.Glu89fs 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-ile841fs (accessed [today's date]).

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