Is CIZ1 p.Pro399= (c.1197G>A) pathogenic?

CIZ1 p.Pro399= (c.1197G>A) is classified Benign/Likely benign in CIZ1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-17). Rare (popmax 0.486%, afr); Associated with dystonic disorder.

What condition is associated with CIZ1 p.Pro399= (c.1197G>A)?

CIZ1 p.Pro399= (c.1197G>A) is associated with dystonic disorder (ClinVar).

How common is CIZ1 p.Pro399= (c.1197G>A) in the general population?

CIZ1 p.Pro399= (c.1197G>A) is rare (popmax 0.486%, afr) (gnomAD).

CIZ1 p.Pro399=

c.1197G>A · rs139585516 · VCV695630

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.486%, afr)

Conditions

dystonic disorder

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 -1.7	GERP -2.6, phastCons 0.037
Overall
CADD	4.313	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.486% African / African-American · 364/74,834 alleles

Filtering AF 0.445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.429%

Overall 0.0364% 587/1,611,470 alleles · rare exomes 380/1,459,704 · genomes 207/151,766 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.486%	206
Remaining individualsnot grpmax-eligible	0.0481%	2,080
South Asian	0.0475%	2,107
East Asian	0.0404%	2,473
Middle Eastern	0.033%	3,030
European (non-Finnish)	0.0105%	9,507
Admixed American	0.01%	9,994

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: CIZ1
Protein: p.Pro399=
Coding: c.1197G>A
MANE Select: NM_001131016
dbSNP: rs139585516
Type: single nucleotide variant
Location: chr9:128179010 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.51 · 1 PDB
Residue 399: the 'disordered' region

Full CIZ1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dystonic disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIZ1 p.Pro399Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CIZ1 p.Ala128Ser Uncertain significance ★★ ⚠ same condition
CIZ1 p.Ala345Val Uncertain significance ★★ ⚠ same condition
CIZ1 p.Ala523Ser Uncertain significance ★★ ⚠ same condition
CIZ1 p.Ala833Gly Uncertain significance ★★ ⚠ same condition
CIZ1 p.Arg286Gln Uncertain significance ★★ ⚠ same condition
CIZ1 p.Arg571His Uncertain significance ★★ ⚠ same condition
CIZ1 p.Arg640Gln Uncertain significance ★★ ⚠ 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/ciz1-p-pro399 (accessed [today's date]).

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