Is CP p.Phe660Leu (c.1978T>C) pathogenic?

CP p.Phe660Leu (c.1978T>C) is classified Uncertain significance in CP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-15). AlphaMissense: likely pathogenic (0.9329); Very rare (popmax 0.00167%, amr).

How common is CP p.Phe660Leu (c.1978T>C) in the general population?

CP p.Phe660Leu (c.1978T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CP p.Phe660Leu (c.1978T>C)?

AlphaMissense predicts likely pathogenic (score 0.9329) — an in-silico prediction, not a clinical call.

CP p.Phe660Leu

c.1978T>C · VCV3573631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9329 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9329	likely pathogenic · top 6% in CP
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -9.27	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 25 kb · p 2.5e-07 · regional, not allelic
Overall
CADD	26.6	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 0.00167% Admixed American · 1/60,012 alleles

Overall 6.84e-05% 1/1,461,882 alleles · very rare

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.Phe660Leu
Coding: c.1978T>C
MANE Select: NM_000096
Type: single nucleotide variant
Location: chr3:149186619 (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 660: a β-strand; the plastocyanin-like 4 domain; a disulfide bond

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

Similar variants

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
CP p.Val219Glu 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-phe660leu (accessed [today's date]).

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