Is CPVL p.Arg464Gln (c.1391G>A) pathogenic?

CPVL p.Arg464Gln (c.1391G>A) is classified Likely benign in CPVL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-05-09). AlphaMissense: ambiguous (0.359); Rare (popmax 0.519%, nfe).

How common is CPVL p.Arg464Gln (c.1391G>A) in the general population?

CPVL p.Arg464Gln (c.1391G>A) is rare (popmax 0.519%, nfe) (gnomAD).

What do computational predictors say about CPVL p.Arg464Gln (c.1391G>A)?

AlphaMissense predicts ambiguous (score 0.359) — an in-silico prediction, not a clinical call.

CPVL p.Arg464Gln

c.1391G>A · rs147771477 · VCV733777

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.359 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.519%, nfe)

Computational evidence

Protein change
AlphaMissense	0.359	ambiguous
REVEL	0.624	indeterminate
SaProt	LLR -12.20	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 125 kb · p 0.072 · regional, not allelic
Overall
CADD	27.1	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 0.519% European (non-Finnish) · 6,110/1,177,654 alleles

Filtering AF 0.508% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.503%

Overall 0.414% 6,660/1,606,928 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.768%	130
European (non-Finnish)grpmax	0.519%	193
Remaining individualsnot grpmax-eligible	0.238%	421
Finnishnot grpmax-eligible	0.218%	460
South Asian	0.128%	784
Admixed American	0.122%	821
African / African-American	0.0831%	1,204
Middle Eastern	0.0171%	5,854
East Asian	0.0112%	8,911
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,845

Amish 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: CPVL
Protein: p.Arg464Gln
Coding: c.1391G>A
MANE Select: NM_031311
dbSNP: rs147771477
Type: single nucleotide variant
Location: chr7:28995812 (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.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
CPVL p.Arg29Gly 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-arg464gln (accessed [today's date]).

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