Is APOB p.Ala4148Asp (c.12443C>A) pathogenic?

APOB p.Ala4148Asp (c.12443C>A) is classified Uncertain significance in APOB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-31). AlphaMissense: ambiguous (0.4854); Ultra-rare (popmax 0.0168%, mid); Associated with hypercholesterolemia, autosomal dominant, type B.

How common is APOB p.Ala4148Asp (c.12443C>A) in the general population?

APOB p.Ala4148Asp (c.12443C>A) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about APOB p.Ala4148Asp (c.12443C>A)?

AlphaMissense predicts ambiguous (score 0.4854) — an in-silico prediction, not a clinical call.

APOB p.Ala4148Asp

Q: What condition is associated with APOB p.Ala4148Asp (c.12443C>A)?

APOB p.Ala4148Asp (c.12443C>A) is associated with hypercholesterolemia, autosomal dominant, type B, familial hypobetalipoproteinemia 1 (ClinVar).

c.12443C>A · rs756476242 · VCV334077

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4854 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Conditions

hypercholesterolemia, autosomal dominant, type B

Computational evidence

Protein change
AlphaMissense	0.4854	ambiguous
REVEL	0.047	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP -1.5, phastCons 0.15
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	18.49	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 0.0168% Middle Eastern · 1/5,962 alleles

Filtering AF 0.00269% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00238%

Overall 0.00282% 45/1,595,410 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,962
European (non-Finnish)	0.00359%	27,844
Admixed American	0.00171%	58,378
African / African-American	0.00135%	74,326

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.Ala4148Asp
Coding: c.12443C>A
MANE Select: NM_000384
dbSNP: rs756476242
Type: single nucleotide variant
Location: chr2:21002979 (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.Ala4148= Conflicting classifications of pathogenicity ★ same residue
APOB p.Ala4148Glu Uncertain significance ★★ same residue
APOB p.Ala4148Thr 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

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-ala4148asp (accessed [today's date]).

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