Is CSPP1 p.Ile224= (c.672C>T) pathogenic?

CSPP1 p.Ile224= (c.672C>T) is classified Conflicting classifications of pathogenicity in CSPP1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-07). Ultra-rare (popmax 0.0451%, sas); Associated with Joubert syndrome 21.

What condition is associated with CSPP1 p.Ile224= (c.672C>T)?

CSPP1 p.Ile224= (c.672C>T) is associated with Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Ile224= (c.672C>T) in the general population?

CSPP1 p.Ile224= (c.672C>T) is ultra-rare (popmax 0.0451%, sas) (gnomAD).

CSPP1 p.Ile224=

c.672C>T · rs372197172 · VCV2047471

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0451%, sas)

Conditions

Joubert syndrome 21

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.47	GERP -2.5, phastCons 1
Overall
CADD	9.319	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0451% South Asian · 41/90,980 alleles

Filtering AF 0.0341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0303%

Overall 0.00812% 131/1,612,784 alleles · ultra-rare exomes 128/1,461,332 · genomes 3/151,452 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0451%	2,219
East Asian	0.0156%	6,402
Remaining individualsnot grpmax-eligible	0.00961%	10,411
European (non-Finnish)	0.00653%	15,320

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.Ile224=
Coding: c.672C>T
MANE Select: NM_001382391
dbSNP: rs372197172
Type: single nucleotide variant
Location: chr8:67095481 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 57.34
Residue 224: the 'disordered' region

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-ile224 (accessed [today's date]).

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