Is CP p.Pro196Leu (c.587C>T) pathogenic?

CP p.Pro196Leu (c.587C>T) is classified Uncertain significance in CP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-09). AlphaMissense: ambiguous (0.4509); Very rare (popmax 0.00329%, sas).

How common is CP p.Pro196Leu (c.587C>T) in the general population?

CP p.Pro196Leu (c.587C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about CP p.Pro196Leu (c.587C>T)?

AlphaMissense predicts ambiguous (score 0.4509) — an in-silico prediction, not a clinical call.

CP p.Pro196Leu

c.587C>T · rs386134124 · VCV3233550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4509 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4509	ambiguous
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -12.63	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.56 · regional, not allelic
Overall
CADD	28.4	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 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00062% 10/1,613,810 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592
South Asiangrpmax	0.00329%	30,361
European (non-Finnish)	0.000509%	196,650

Ashkenazi Jewish 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.Pro196Leu
Coding: c.587C>T
MANE Select: NM_000096
dbSNP: rs386134124
Type: single nucleotide variant
Location: chr3:149210187 (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 196: the plastocyanin-like 1 domain; a disulfide bond; a β-strand

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

Similar variants

CP p.Pro196Arg Pathogenic same residue
CP c.1208+1G>A Pathogenic ★★ same type
CP c.2879-1G>T Likely pathogenic ★★ same type
CP p.Arg901Ter Pathogenic ★★ same type
CP p.Gly195Arg Likely pathogenic ★★ same type
CP p.Gly650Arg Pathogenic/Likely pathogenic ★★ same type
CP p.Gly708Ser Pathogenic ★★ same type
CP p.Leu919Pro Pathogenic/Likely pathogenic ★★ same type

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-pro196leu (accessed [today's date]).

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