Is CSPP1 p.Arg994Gln (c.2981G>A) pathogenic?

CSPP1 p.Arg994Gln (c.2981G>A) is classified Uncertain significance in CSPP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-31). Ultra-rare (popmax 0.0123%, nfe); Associated with Joubert syndrome 21.

What condition is associated with CSPP1 p.Arg994Gln (c.2981G>A)?

CSPP1 p.Arg994Gln (c.2981G>A) is associated with Joubert syndrome 21 (ClinVar).

How common is CSPP1 p.Arg994Gln (c.2981G>A) in the general population?

CSPP1 p.Arg994Gln (c.2981G>A) is ultra-rare (popmax 0.0123%, nfe) (gnomAD).

CSPP1 p.Arg994Gln

c.2981G>A · rs367949127 · VCV939297

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Conditions

Joubert syndrome 21

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.206	benign-leaning
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 121 kb · p 0.15 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0123% European (non-Finnish) · 145/1,176,952 alleles

Filtering AF 0.0107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00999%

Overall 0.00951% 153/1,608,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0123%	8,117
Remaining individualsnot grpmax-eligible	0.00482%	20,762
Admixed American	0.00338%	29,629
East Asian	0.00223%	44,856
Finnishnot grpmax-eligible	0.00156%	63,980
African / African-American	0.00134%	74,620

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.Arg994Gln
Coding: c.2981G>A
MANE Select: NM_006421 · reported on NM_001382391
dbSNP: rs367949127
Type: single nucleotide variant
Location: chr8:67175308 (GRCh38)

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

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-arg994gln (accessed [today's date]).

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