Is APOB p.Ala43= (c.129G>C) pathogenic?

APOB p.Ala43= (c.129G>C) is classified Benign/Likely benign in APOB (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-27). Low-frequency (popmax 2.09%, afr); Associated with hypercholesterolemia, autosomal dominant, type B.

What condition is associated with APOB p.Ala43= (c.129G>C)?

APOB p.Ala43= (c.129G>C) is associated with hypercholesterolemia, autosomal dominant, type B, familial hypercholesterolemia, familial hypobetalipoproteinemia 1 (ClinVar).

How common is APOB p.Ala43= (c.129G>C) in the general population?

APOB p.Ala43= (c.129G>C) is low-frequency (popmax 2.09%, afr) (gnomAD).

APOB p.Ala43=

c.129G>C · rs12720850 · VCV334189

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.09%, afr)

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 -0.76	GERP -3.5, phastCons 0.018
Overall
CADD	6.616	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.09% African / African-American · 1,570/74,988 alleles

Filtering AF 2.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.97%

Overall 0.11% 1,777/1,613,884 alleles · low-frequency exomes 888/1,461,678 · genomes 889/152,206 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.09%	48
Admixed American	0.125%	800
Remaining individualsnot grpmax-eligible	0.123%	812
Middle Eastern	0.099%	1,010
South Asian	0.00549%	18,213
European (non-Finnish)	0.00373%	26,815

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.Ala43=
Coding: c.129G>C
MANE Select: NM_000384
dbSNP: rs12720850
Type: single nucleotide variant
Location: chr2:21042469 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 43: the 'heparin-binding' region

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.Ala43Glu Uncertain significance ★ ⚠ same residue
APOB p.Ala43Val Uncertain significance ★ ⚠ 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-ala43 (accessed [today's date]).

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