Is CP p.Val175Leu (c.523G>T) pathogenic?

CP p.Val175Leu (c.523G>T) is classified Uncertain significance in CP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.219); Very rare (popmax 0.00314%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CP p.Val175Leu (c.523G>T)?

CP p.Val175Leu (c.523G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CP p.Val175Leu (c.523G>T) in the general population?

CP p.Val175Leu (c.523G>T) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about CP p.Val175Leu (c.523G>T)?

AlphaMissense predicts likely benign (score 0.219) — an in-silico prediction, not a clinical call.

CP p.Val175Leu

c.523G>T · VCV4006019

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.219 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.219	likely benign
REVEL	0.364	indeterminate
SaProt	LLR -3.24	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 4.1	GERP 2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.56 · regional, not allelic
Overall
CADD	15.79	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 0.00314% European (non-Finnish) · 37/1,179,956 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00242% 39/1,613,964 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,891
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00156%	64,044

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.Val175Leu
Coding: c.523G>T
MANE Select: NM_000096
Type: single nucleotide variant
Location: chr3:149210251 (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 175: 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

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-val175leu (accessed [today's date]).

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