Is CSPP1 p.Arg517Ter (c.1549C>T) pathogenic?

CSPP1 p.Arg517Ter (c.1549C>T) is classified Pathogenic in CSPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-27). Very rare (popmax 0.0033%, sas); Associated with Joubert syndrome 21.

What condition is associated with CSPP1 p.Arg517Ter (c.1549C>T)?

CSPP1 p.Arg517Ter (c.1549C>T) is associated with Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Arg517Ter (c.1549C>T) in the general population?

CSPP1 p.Arg517Ter (c.1549C>T) is very rare (popmax 0.0033%, sas) (gnomAD).

CSPP1 p.Arg517Ter

c.1549C>T · rs756752153 · VCV860634

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

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 14 of 31
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.068, phastCons 1
Overall
CADD	35.0	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 0.0033% South Asian · 3/91,044 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000372% 6/1,613,310 alleles · very rare exomes 6/1,461,076 · genomes 0/152,234 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,348
Admixed American	0.00167%	60,008
European (non-Finnish)	0.00017%	589,685

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.Arg517Ter
Coding: c.1549C>T
MANE Select: NM_001382391
dbSNP: rs756752153
Type: single nucleotide variant
Location: chr8:67118300 (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.Arg517Gln Uncertain significance ★ same residue
CSPP1 p.Arg517= Likely benign ★ 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

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-arg517ter (accessed [today's date]).

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