Is CP p.Pro604His (c.1811C>A) pathogenic?

CP p.Pro604His (c.1811C>A) is classified Uncertain significance in CP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-25). AlphaMissense: likely benign (0.1821); Rare (popmax 0.223%, amr); Associated with Inborn genetic diseases.

What condition is associated with CP p.Pro604His (c.1811C>A)?

CP p.Pro604His (c.1811C>A) is associated with Inborn genetic diseases, aceruloplasminemia (ClinVar).

How common is CP p.Pro604His (c.1811C>A) in the general population?

CP p.Pro604His (c.1811C>A) is rare (popmax 0.223%, amr) (gnomAD).

What do computational predictors say about CP p.Pro604His (c.1811C>A)?

AlphaMissense predicts likely benign (score 0.1821) — an in-silico prediction, not a clinical call.

CP p.Pro604His

c.1811C>A · rs188643164 · VCV952095

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1821 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.223%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1821	likely benign
REVEL	0.648	pathogenic-leaning
SaProt	LLR -14.59	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 25 kb · p 2.5e-07 · regional, not allelic
Overall
CADD	24.6	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 0.223% Admixed American · 134/60,026 alleles

Filtering AF 0.192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.181%

Overall 0.00893% 144/1,612,502 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.223%	448
Remaining individualsnot grpmax-eligible	0.0112%	8,912
African / African-American	0.004%	24,997

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.Pro604His
Coding: c.1811C>A
MANE Select: NM_000096
dbSNP: rs188643164
Type: single nucleotide variant
Location: chr3:149188105 (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 604: an α-helix; the plastocyanin-like 4 domain

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

Disease context

Inborn genetic diseases — 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 p.Val219Glu Likely 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-pro604his (accessed [today's date]).

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