Is CPVL p.Arg433Trp (c.1297C>T) pathogenic?

CPVL p.Arg433Trp (c.1297C>T) is classified Uncertain significance in CPVL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-04). AlphaMissense: ambiguous (0.371); Ultra-rare (popmax 0.0165%, mid).

How common is CPVL p.Arg433Trp (c.1297C>T) in the general population?

CPVL p.Arg433Trp (c.1297C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CPVL p.Arg433Trp (c.1297C>T)?

AlphaMissense predicts ambiguous (score 0.371) — an in-silico prediction, not a clinical call.

CPVL p.Arg433Trp

c.1297C>T · VCV4233625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.371 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.371	ambiguous
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -11.54	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 3.9	GERP 0.63, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 125 kb · p 0.072 · regional, not allelic
Overall
CADD	24.5	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00589% 95/1,612,574 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
Remaining individualsnot grpmax-eligible	0.00801%	12,486
European (non-Finnish)	0.00695%	14,383
African / African-American	0.00534%	18,714
South Asian	0.00331%	30,252

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: CPVL
Protein: p.Arg433Trp
Coding: c.1297C>T
MANE Select: NM_031311
Type: single nucleotide variant
Location: chr7:29030600 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.55

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

Similar variants

CPVL p.Arg464Gln Likely benign ★★ ⚠ same type
CPVL p.Met5Thr Likely benign ★★ same type
CPVL p.Ala234Val Uncertain significance ★ ⚠ same type
CPVL p.Ala341Thr Uncertain significance ★ ⚠ same type
CPVL p.Arg136Cys Uncertain significance ★ ⚠ same type
CPVL p.Arg136His Uncertain significance ★ ⚠ same type
CPVL p.Arg136Pro Uncertain significance ★ ⚠ same type
CPVL p.Arg177Pro Uncertain significance ★ ⚠ 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/cpvl-p-arg433trp (accessed [today's date]).

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