Is APOB p.Ala4148= (c.12444C>A) pathogenic?

APOB p.Ala4148= (c.12444C>A) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-06-01). Ultra-rare (popmax 0.0168%, mid); Associated with hypercholesterolemia, autosomal dominant, type B.

What condition is associated with APOB p.Ala4148= (c.12444C>A)?

APOB p.Ala4148= (c.12444C>A) is associated with hypercholesterolemia, autosomal dominant, type B, familial hypercholesterolemia, familial hypobetalipoproteinemia 1 (ClinVar).

How common is APOB p.Ala4148= (c.12444C>A) in the general population?

APOB p.Ala4148= (c.12444C>A) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

APOB p.Ala4148=

c.12444C>A · rs757789853 · VCV334076

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Conditions

hypercholesterolemia, autosomal dominant, type B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -3.4, phastCons 0.57
Overall
CADD	5.374	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% Middle Eastern · 1/5,964 alleles

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

Overall 0.00282% 45/1,595,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,964
European (non-Finnish)	0.00359%	27,853
Admixed American	0.00171%	58,390
African / African-American	0.00135%	74,312

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.Ala4148=
Coding: c.12444C>A
MANE Select: NM_000384
dbSNP: rs757789853
Type: single nucleotide variant
Location: chr2:21002978 (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 hypercholesterolemia familial hypobetalipoproteinemia 1

Similar variants

APOB p.Ala4148Asp Uncertain significance ★★ ⚠ 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-ala4148 (accessed [today's date]).

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