Is APOB p.Arg1815Trp (c.5443C>T) pathogenic?

APOB p.Arg1815Trp (c.5443C>T) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.1213); Very rare (popmax 0.00668%, eas); Associated with hypercholesterolemia, autosomal dominant, type B.

How common is APOB p.Arg1815Trp (c.5443C>T) in the general population?

APOB p.Arg1815Trp (c.5443C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about APOB p.Arg1815Trp (c.5443C>T)?

AlphaMissense predicts likely benign (score 0.1213) — an in-silico prediction, not a clinical call.

APOB p.Arg1815Trp

Q: What condition is associated with APOB p.Arg1815Trp (c.5443C>T)?

APOB p.Arg1815Trp (c.5443C>T) is associated with hypercholesterolemia, autosomal dominant, type B, familial hypobetalipoproteinemia 1 (ClinVar).

c.5443C>T · rs144341880 · VCV2924040

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hypercholesterolemia, autosomal dominant, type B

Computational evidence

Protein change
AlphaMissense	0.1213	likely benign
REVEL	0.158	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 5.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 272 bp · p 0.00033 · regional, not allelic
Overall
CADD	25.0	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 0.00668% East Asian · 3/44,900 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00192% 31/1,613,964 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,967
South Asian	0.0022%	45,544
European (non-Finnish)	0.00212%	47,201
Admixed American	0.00167%	60,000

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.Arg1815Trp
Coding: c.5443C>T
MANE Select: NM_000384
dbSNP: rs144341880
Type: single nucleotide variant
Location: chr2:21011425 (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

hypercholesterolemia, autosomal dominant, type B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypobetalipoproteinemia 1

Similar variants

APOB p.Arg1815Gln 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
APOB p.Arg2513Ter 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-arg1815trp (accessed [today's date]).

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