Is CP p.Val219Glu (c.656T>A) pathogenic?

CP p.Val219Glu (c.656T>A) is classified Likely pathogenic in CP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-11). AlphaMissense: likely pathogenic (0.8695); Very rare (popmax 0.0028%, nfe); Associated with neurodegeneration with brain iron accumulation.

What condition is associated with CP p.Val219Glu (c.656T>A)?

CP p.Val219Glu (c.656T>A) is associated with neurodegeneration with brain iron accumulation, aceruloplasminemia (ClinVar).

How common is CP p.Val219Glu (c.656T>A) in the general population?

CP p.Val219Glu (c.656T>A) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about CP p.Val219Glu (c.656T>A)?

AlphaMissense predicts likely pathogenic (score 0.8695) — an in-silico prediction, not a clinical call.

CP p.Val219Glu

c.656T>A · rs587780321 · VCV128844

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8695 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodegeneration with brain iron accumulation

Computational evidence

Protein change
AlphaMissense	0.8695	likely pathogenic ✓ concordant with ClinVar
REVEL	0.779	moderately pathogenic-leaning
SaProt	LLR -11.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.30	acceptor loss, 31 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.3	GERP 2.2, phastCons 0.66
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.56 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0028% European (non-Finnish) · 33/1,179,778 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00223% 36/1,613,654 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,234
European (non-Finnish)grpmax	0.0028%	35,751
African / African-American	0.00134%	74,896

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val219Glu
Coding: c.656T>A
MANE Select: NM_000096
dbSNP: rs587780321
Type: single nucleotide variant
Location: chr3:149209336 (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 219: the plastocyanin-like 2 domain; a β-strand

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 c.1208+1G>A Pathogenic ★★ same condition
CP c.2879-1G>T Likely pathogenic ★★ same condition
CP p.Arg901Ter Pathogenic ★★ same condition
CP p.Gly195Arg Likely pathogenic ★★ same condition
CP p.Gly650Arg Pathogenic/Likely pathogenic ★★ same condition
CP p.Gly708Ser Pathogenic ★★ same condition
CP p.Leu919Pro Pathogenic/Likely pathogenic ★★ same condition
CP c.1037-3C>A 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/cp-p-val219glu (accessed [today's date]).

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