Is CSPP1 p.Pro1153Ser (c.3457C>T) pathogenic?

CSPP1 p.Pro1153Ser (c.3457C>T) is classified Uncertain significance in CSPP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-18). Ultra-rare (popmax 0.0661%, mid); Associated with Joubert syndrome 21.

What condition is associated with CSPP1 p.Pro1153Ser (c.3457C>T)?

CSPP1 p.Pro1153Ser (c.3457C>T) is associated with Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Pro1153Ser (c.3457C>T) in the general population?

CSPP1 p.Pro1153Ser (c.3457C>T) is ultra-rare (popmax 0.0661%, mid) (gnomAD).

CSPP1 p.Pro1153Ser

c.3457C>T · rs181079660 · VCV1517301

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, mid)

Conditions

Joubert syndrome 21

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.045	moderately benign-leaning
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.59	GERP -1.7, phastCons 0.005
Regional constraint	o/e 0.96	unconstrained · MANE · 121 kb · p 0.15 · regional, not allelic
Overall
CADD	12.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0661% Middle Eastern · 4/6,056 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00762% 123/1,613,210 alleles · ultra-rare exomes 110/1,460,920 · genomes 13/152,290 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0661%	1,514
South Asian	0.0461%	2,167
Remaining individualsnot grpmax-eligible	0.0128%	7,808
Finnishnot grpmax-eligible	0.00626%	15,972
European (non-Finnish)	0.00526%	19,023
Admixed American	0.00333%	30,007
African / African-American	0.00133%	74,990

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.Pro1153Ser
Coding: c.3457C>T
MANE Select: NM_001382391
dbSNP: rs181079660
Type: single nucleotide variant
Location: chr8:67193590 (GRCh38)

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

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-pro1153ser (accessed [today's date]).

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