Is APOB p.Pro3133= (c.9399T>C) pathogenic?

APOB p.Pro3133= (c.9399T>C) is classified Benign in APOB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-12). Very rare (popmax 0.004%, afr); Associated with familial hypobetalipoproteinemia 1.

What condition is associated with APOB p.Pro3133= (c.9399T>C)?

APOB p.Pro3133= (c.9399T>C) is associated with familial hypobetalipoproteinemia 1, hypercholesterolemia, autosomal dominant, type B (ClinVar).

How common is APOB p.Pro3133= (c.9399T>C) in the general population?

APOB p.Pro3133= (c.9399T>C) is very rare (popmax 0.004%, afr) (gnomAD).

APOB p.Pro3133=

c.9399T>C · VCV4787766

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

familial hypobetalipoproteinemia 1

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 1.4	GERP 0.57, phastCons 1
Overall
CADD	5.753	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,930 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00031% 5/1,613,990 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,977
European (non-Finnish)	0.000169%	589,988

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.Pro3133=
Coding: c.9399T>C
MANE Select: NM_000384
Type: single nucleotide variant
Location: chr2:21007469 (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

familial hypobetalipoproteinemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, autosomal dominant, type B

Similar variants

APOB p.Pro3133Leu 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
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-pro3133 (accessed [today's date]).

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