Is APOB p.Arg3527Trp (c.10579C>T) pathogenic?

APOB p.Arg3527Trp (c.10579C>T) is classified Pathogenic/Likely pathogenic in APOB (ClinVar, Multiple submitters, 37 submitters; last evaluated 2026-07-08). AlphaMissense: likely benign (0.2214); Ultra-rare (popmax 0.0513%, eas); Associated with homozygous familial hypercholesterolemia.

What condition is associated with APOB p.Arg3527Trp (c.10579C>T)?

APOB p.Arg3527Trp (c.10579C>T) is associated with homozygous familial hypercholesterolemia, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is APOB p.Arg3527Trp (c.10579C>T) in the general population?

APOB p.Arg3527Trp (c.10579C>T) is ultra-rare (popmax 0.0513%, eas) (gnomAD).

How is Homozygous familial hypercholesterolemia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about APOB p.Arg3527Trp (c.10579C>T)?

AlphaMissense predicts likely benign (score 0.2214) — an in-silico prediction, not a clinical call.

APOB p.Arg3527Trp

c.10579C>T · rs144467873 · VCV40223

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 37 submitters

AlphaMissense

likely benign

0.2214 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0513%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

homozygous familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.2214	likely benign ⚠ discordant with ClinVar
REVEL	0.854	moderately pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	25.3	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 0.0513% East Asian · 23/44,872 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.00576% 93/1,613,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0513%	1,951
South Asian	0.0384%	2,602
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.0028%	35,756
African / African-American	0.00133%	75,006

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.Arg3527Trp
Coding: c.10579C>T
MANE Select: NM_000384
dbSNP: rs144467873
Type: single nucleotide variant
Location: chr2:21006289 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 3527: a UniProt-annotated variant site (in fhcl2)

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

Disease context

homozygous familial hypercholesterolemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Homozygous familial hypercholesterolemia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

APOB p.Arg3527Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
APOB p.Arg3527= Likely benign ★★ same residue
APOB p.Arg3527Leu Likely pathogenic ★ ⚠ 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

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-arg3527trp (accessed [today's date]).

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