Is APOB p.Arg490Trp (c.1468C>T) pathogenic?

APOB p.Arg490Trp (c.1468C>T) is classified Pathogenic/Likely pathogenic in APOB (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-09). AlphaMissense: ambiguous (0.4657); Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Arg490Trp (c.1468C>T)?

APOB p.Arg490Trp (c.1468C>T) is associated with Cardiovascular phenotype, hypercholesterolemia, autosomal dominant, type B, familial hypobetalipoproteinemia 1 (ClinVar).

How common is APOB p.Arg490Trp (c.1468C>T) in the general population?

APOB p.Arg490Trp (c.1468C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about APOB p.Arg490Trp (c.1468C>T)?

AlphaMissense predicts ambiguous (score 0.4657) — an in-silico prediction, not a clinical call.

APOB p.Arg490Trp

c.1468C>T · rs771541567 · VCV1685527

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.4657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4657	ambiguous
REVEL	0.563	indeterminate
Splicing
SpliceAI	Δ0.98	donor gain · deltas
Pangolin	Δ0.74	gain · loss 0.55 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.4	GERP -1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	36.0	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 0.0011% South Asian · 1/91,010 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000823% 12/1,458,508 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,010
European (non-Finnish)	0.000934%	107,025

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: APOB
Protein: p.Arg490Trp
Coding: c.1468C>T
MANE Select: NM_000384
dbSNP: rs771541567
Type: single nucleotide variant
Location: chr2:21029900 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 490: the vitellogenin domain; a disulfide bond; a UniProt-annotated variant site (in fhbl1; reduced protein secretion)

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, autosomal dominant, type B familial hypobetalipoproteinemia 1

Similar variants

APOB p.Arg490Gln Uncertain significance ★★ same residue
APOB p.Arg490= Likely benign ★★ same residue
APOB c.1830-1G>A Pathogenic ★★ same condition
APOB c.2604+1G>A Likely pathogenic ★★ same condition
APOB c.537+1G>T Pathogenic/Likely pathogenic ★★ same condition
APOB p.Arg1333Ter Pathogenic ★★ same condition
APOB p.Arg2012Ter Pathogenic ★★ same condition
APOB p.Arg2085Ter Pathogenic/Likely pathogenic ★★ 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/apob-p-arg490trp (accessed [today's date]).

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