Is CSPP1 p.Pro462Ser (c.1384C>T) pathogenic?

CSPP1 p.Pro462Ser (c.1384C>T) is classified Uncertain significance in CSPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-23). Ultra-rare (popmax 0.0428%, sas); Associated with Joubert syndrome 21.

What condition is associated with CSPP1 p.Pro462Ser (c.1384C>T)?

CSPP1 p.Pro462Ser (c.1384C>T) is associated with Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Pro462Ser (c.1384C>T) in the general population?

CSPP1 p.Pro462Ser (c.1384C>T) is ultra-rare (popmax 0.0428%, sas) (gnomAD).

CSPP1 p.Pro462Ser

c.1384C>T · rs546837200 · VCV1953753

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0428%, sas)

Conditions

Joubert syndrome 21

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.053	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 121 kb · p 0.15 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0428% South Asian · 39/91,078 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0284%

Overall 0.00254% 41/1,614,004 alleles · ultra-rare exomes 36/1,461,720 · genomes 5/152,284 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0428%	2,335
African / African-American	0.00267%	37,522

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.Pro462Ser
Coding: c.1384C>T
MANE Select: NM_001382391
dbSNP: rs546837200
Type: single nucleotide variant
Location: chr8:67116010 (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 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
CSPP1 c.-69C>T Pathogenic/Likely 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-pro462ser (accessed [today's date]).

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