Is CP p.Pro689fs (c.2066del) pathogenic?

CP p.Pro689fs (c.2066del) is classified Pathogenic/Likely pathogenic in CP (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-22). Ultra-rare (popmax 0.0131%, nfe); Associated with neurodegeneration with brain iron accumulation.

What condition is associated with CP p.Pro689fs (c.2066del)?

CP p.Pro689fs (c.2066del) is associated with neurodegeneration with brain iron accumulation, aceruloplasminemia (ClinVar).

How common is CP p.Pro689fs (c.2066del) in the general population?

CP p.Pro689fs (c.2066del) is ultra-rare (popmax 0.0131%, nfe) (gnomAD).

CP p.Pro689fs

c.2066del · rs386134147 · VCV42143

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, nfe)

Conditions

neurodegeneration with brain iron accumulation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.2	GERP -4.1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0131% European (non-Finnish) · 155/1,179,978 alleles

Filtering AF 0.0114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.00967% 156/1,614,030 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0131%	7,613
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: CP
Protein: p.Pro689fs
Coding: c.2066del
MANE Select: NM_000096
dbSNP: rs386134147
Type: Deletion
Location: chr3:149186531 (GRCh38)
Gene constraint: LOEUF 0.624 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.79 · 4 PDB
Residue 689: the plastocyanin-like 4 domain; a disulfide bond

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

Disease context

neurodegeneration with brain iron accumulation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: aceruloplasminemia

Similar variants

CP p.Pro689Ser Uncertain significance ★★ ⚠ same residue
CP c.607+1del Pathogenic/Likely pathogenic ★★ same condition
CP p.Met1* Uncertain significance ★★ same condition
CP c.2286-15_2286-14del Benign/Likely benign ★★ same condition
CP c.2286-15del Benign ★★ same condition
CP c.2286-4del Benign/Likely benign ★★ same condition
CP c.2078-75_2241del Likely pathogenic ★ same condition
CP p.Ala675fs 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/cp-p-pro689fs (accessed [today's date]).

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