Is CSPP1 p.Arg759Ter (c.2275C>T) pathogenic?

CSPP1 p.Arg759Ter (c.2275C>T) is classified Pathogenic in CSPP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-02). Very rare (popmax 0.00223%, eas); Associated with Joubert syndrome 21.

What condition is associated with CSPP1 p.Arg759Ter (c.2275C>T)?

CSPP1 p.Arg759Ter (c.2275C>T) is associated with Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Arg759Ter (c.2275C>T) in the general population?

CSPP1 p.Arg759Ter (c.2275C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

CSPP1 p.Arg759Ter

c.2275C>T · rs771203308 · VCV217648

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Joubert syndrome 21

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 20 of 31
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 2, phastCons 1
Overall
CADD	37.0	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 0.00223% East Asian · 1/44,794 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000959% 14/1,459,466 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,794
South Asian	0.0011%	90,722
European (non-Finnish)	0.00102%	98,208

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.Arg759Ter
Coding: c.2275C>T
MANE Select: NM_001382391
dbSNP: rs771203308
Type: single nucleotide variant
Location: chr8:67158480 (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.Arg759Gln Uncertain significance ★ same residue
CSPP1 c.1022+1G>T Likely pathogenic ★★ same condition
CSPP1 c.1187+1G>A Pathogenic/Likely pathogenic ★★ same condition
CSPP1 c.1497-2A>C Likely pathogenic ★★ same condition
CSPP1 c.1697+1G>T Pathogenic/Likely pathogenic ★★ same condition
CSPP1 c.2968+1G>A Pathogenic ★★ same condition
CSPP1 c.2968+1G>T Pathogenic ★★ same condition
CSPP1 c.923+1G>C 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-arg759ter (accessed [today's date]).

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