Is APOB p.Arg1867Trp (c.5599C>T) pathogenic?

APOB p.Arg1867Trp (c.5599C>T) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.1683); Ultra-rare (popmax 0.0347%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Arg1867Trp (c.5599C>T)?

APOB p.Arg1867Trp (c.5599C>T) is associated with Cardiovascular phenotype, hypercholesterolemia, familial, 1, hypercholesterolemia, autosomal dominant, type B (ClinVar).

How common is APOB p.Arg1867Trp (c.5599C>T) in the general population?

APOB p.Arg1867Trp (c.5599C>T) is ultra-rare (popmax 0.0347%, nfe) (gnomAD).

What do computational predictors say about APOB p.Arg1867Trp (c.5599C>T)?

AlphaMissense predicts likely benign (score 0.1683) — an in-silico prediction, not a clinical call.

APOB p.Arg1867Trp

c.5599C>T · rs200583769 · VCV265887

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1683 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1683	likely benign
REVEL	0.18	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	25.5	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 0.0347% European (non-Finnish) · 409/1,180,018 alleles

Filtering AF 0.0319% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0307%

Overall 0.027% 435/1,614,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0347%	2,885
Remaining individualsnot grpmax-eligible	0.016%	6,249
African / African-American	0.00801%	12,489
Finnishnot grpmax-eligible	0.00781%	12,808
Admixed American	0.00667%	14,999
East Asian	0.00223%	44,898

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.Arg1867Trp
Coding: c.5599C>T
MANE Select: NM_000384
dbSNP: rs200583769
Type: single nucleotide variant
Location: chr2:21011269 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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, familial, 1 hypercholesterolemia, autosomal dominant, type B familial hypobetalipoproteinemia 1

Similar variants

APOB p.Arg1867Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
APOB p.Arg1867= 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-arg1867trp (accessed [today's date]).

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