Is CCZ1 p.Pro286His (c.857C>A) pathogenic?

CCZ1 p.Pro286His (c.857C>A) is classified Uncertain significance in CCZ1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). Very rare (popmax 0.000357%, nfe).

How common is CCZ1 p.Pro286His (c.857C>A) in the general population?

CCZ1 p.Pro286His (c.857C>A) is very rare (popmax 0.000357%, nfe) (gnomAD).

CCZ1 p.Pro286His

c.857C>A · VCV3997921

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000357%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.475	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.09	constrained · MANE · 54 bp · p 1.4e-05 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000357% European (non-Finnish) · 4/1,121,104 alleles

Filtering AF 8.4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.6e-05%

Overall 0.000259% 4/1,545,482 alleles · very rare

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: CCZ1
Protein: p.Pro286His
Coding: c.857C>A
MANE Select: NM_015622
Type: single nucleotide variant
Location: chr7:5912857 (GRCh38)
Gene constraint: LOEUF 0.675 · pLI 0.20 (gnomAD)
Structure: AlphaFold pLDDT 89.12 · 1 PDB

Full CCZ1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCZ1 p.Ala224Ser Uncertain significance ★ same type
CCZ1 p.Ala224Val Uncertain significance ★ same type
CCZ1 p.Ala4Val Uncertain significance ★ same type
CCZ1 p.Arg174Gln Uncertain significance ★ same type
CCZ1 p.Arg174Trp Uncertain significance ★ same type
CCZ1 p.Arg269Lys Uncertain significance ★ same type
CCZ1 p.Arg340Gln Uncertain significance ★ same type
CCZ1 p.Arg446Trp Uncertain significance ★ same type

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/ccz1-p-pro286his (accessed [today's date]).

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