Is CP p.Pro522Leu (c.1565C>T) pathogenic?

CP p.Pro522Leu (c.1565C>T) is classified Uncertain significance in CP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.2548); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with CP p.Pro522Leu (c.1565C>T)?

CP p.Pro522Leu (c.1565C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CP p.Pro522Leu (c.1565C>T) in the general population?

CP p.Pro522Leu (c.1565C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CP p.Pro522Leu (c.1565C>T)?

AlphaMissense predicts likely benign (score 0.2548) — an in-silico prediction, not a clinical call.

CP p.Pro522Leu

c.1565C>T · VCV4616445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2548 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2548	likely benign
REVEL	0.639	indeterminate
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
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	26.3	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 0.00223% East Asian · 1/44,880 alleles

Overall 0.000186% 3/1,614,124 alleles · very rare exomes 3/1,461,846 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
Remaining individualsnot grpmax-eligible	0.0016%	62,496
African / African-American	0.00133%	75,024

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.Pro522Leu
Coding: c.1565C>T
MANE Select: NM_000096
Type: single nucleotide variant
Location: chr3:149198515 (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 522: the plastocyanin-like 3 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

Similar variants

CP p.Asn397Lys Uncertain significance ★★ ⚠ same condition
CP p.Asp654Asn Uncertain significance ★★ ⚠ same condition
CP p.Glu742Gln Uncertain significance ★★ ⚠ same condition
CP p.Glu754Lys Uncertain significance ★★ ⚠ same condition
CP p.Glu803Gln Uncertain significance ★★ ⚠ same condition
CP p.Gly730Val Uncertain significance ★★ ⚠ same condition
CP p.Gly967Ala Uncertain significance ★★ ⚠ same condition
CP p.His445Tyr 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-pro522leu (accessed [today's date]).

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