Is CP p.Leu592Phe (c.1774C>T) pathogenic?

CP p.Leu592Phe (c.1774C>T) is classified Uncertain significance in CP (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.0763); Ultra-rare (popmax 0.0826%, eas); Associated with aceruloplasminemia.

What condition is associated with CP p.Leu592Phe (c.1774C>T)?

CP p.Leu592Phe (c.1774C>T) is associated with aceruloplasminemia (ClinVar).

How common is CP p.Leu592Phe (c.1774C>T) in the general population?

CP p.Leu592Phe (c.1774C>T) is ultra-rare (popmax 0.0826%, eas) (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.Leu592Phe (c.1774C>T)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

CP p.Leu592Phe

c.1774C>T · rs200226362 · VCV343763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0826%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

aceruloplasminemia

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -3.73	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 25 kb · p 2.5e-07 · regional, not allelic
Overall
CADD	18.83	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0826% East Asian · 37/44,800 alleles

Filtering AF 0.0616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0543%

Overall 0.0153% 247/1,612,764 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0826%	1,211
European (non-Finnish)	0.0172%	5,810
Remaining individualsnot grpmax-eligible	0.00641%	15,612
African / African-American	0.00267%	37,501
South Asian	0.0011%	91,050

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.Leu592Phe
Coding: c.1774C>T
MANE Select: NM_000096
dbSNP: rs200226362
Type: single nucleotide variant
Location: chr3:149188142 (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 592: the plastocyanin-like 4 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

CP p.Leu592Val Uncertain significance ★★ ⚠ same residue
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

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-leu592phe (accessed [today's date]).

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