Is CSPP1 p.Arg396Ter (c.1186C>T) pathogenic?

CSPP1 p.Arg396Ter (c.1186C>T) is classified Conflicting classifications of pathogenicity in CSPP1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-29). Ultra-rare (popmax 0.036%, eas); Associated with CSPP1-related disorder.

What condition is associated with CSPP1 p.Arg396Ter (c.1186C>T)?

CSPP1 p.Arg396Ter (c.1186C>T) is associated with CSPP1-related disorder, Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Arg396Ter (c.1186C>T) in the general population?

CSPP1 p.Arg396Ter (c.1186C>T) is ultra-rare (popmax 0.036%, eas) (gnomAD).

CSPP1 p.Arg396Ter

c.1186C>T · rs775285273 · VCV1320074

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, eas)

Conditions

CSPP1-related disorder

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 10 of 31
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.7	GERP 1.7, phastCons 1
Overall
CADD	39.0	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 0.036% East Asian · 16/44,468 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0183%

Overall 0.00287% 46/1,601,704 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.036%	2,779
European (non-Finnish)	0.00248%	40,384
Remaining individualsnot grpmax-eligible	0.00161%	61,996

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.Arg396Ter
Coding: c.1186C>T
MANE Select: NM_001382391
dbSNP: rs775285273
Type: single nucleotide variant
Location: chr8:67112064 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 57.34
Residue 396: 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.Arg396Gln Pathogenic/Likely pathogenic ★★ same residue
CSPP1 p.Arg396Pro 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

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-arg396ter (accessed [today's date]).

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