Is CP p.Pro136Leu (c.407C>T) pathogenic?

CP p.Pro136Leu (c.407C>T) is classified Uncertain significance in CP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: ambiguous (0.3764); Very rare (popmax 0.00439%, sas); Associated with aceruloplasminemia.

What condition is associated with CP p.Pro136Leu (c.407C>T)?

CP p.Pro136Leu (c.407C>T) is associated with aceruloplasminemia (ClinVar).

How common is CP p.Pro136Leu (c.407C>T) in the general population?

CP p.Pro136Leu (c.407C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

How is Aceruloplasminemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CP p.Pro136Leu (c.407C>T)?

AlphaMissense predicts ambiguous (score 0.3764) — an in-silico prediction, not a clinical call.

CP p.Pro136Leu

c.407C>T · rs878959339 · VCV568696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

aceruloplasminemia

Computational evidence

Protein change
AlphaMissense	0.3764	ambiguous
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -7.63	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.56 · regional, not allelic
Overall
CADD	25.8	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 0.00439% South Asian · 4/91,070 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000547% 8/1,461,720 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,767
European (non-Finnish)	0.000339%	294,976

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.Pro136Leu
Coding: c.407C>T
MANE Select: NM_000096
dbSNP: rs878959339
Type: single nucleotide variant
Location: chr3:149210367 (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 136: the plastocyanin-like 1 domain

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

Disease context

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

For Aceruloplasminemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult, Elderly
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

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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-pro136leu (accessed [today's date]).

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