Is APOB p.Thr248fs (c.741_745del) pathogenic?

APOB p.Thr248fs (c.741745del) is classified Pathogenic/Likely pathogenic in APOB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-29). Very rare (popmax 8.47e-05%, nfe); Associated with hypercholesterolemia, autosomal dominant, type B.

How common is APOB p.Thr248fs (c.741_745del) in the general population?

APOB p.Thr248fs (c.741_745del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

APOB p.Thr248fs

Q: What condition is associated with APOB p.Thr248fs (c.741_745del)?

APOB p.Thr248fs (c.741_745del) is associated with hypercholesterolemia, autosomal dominant, type B, familial hypobetalipoproteinemia 1 (ClinVar).

c.741_745del · rs1663984693 · VCV2949610

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hypercholesterolemia, autosomal dominant, type B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 29
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.84e-05% 1/1,461,770 alleles · very rare

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.Thr248fs
Coding: c.741_745del
MANE Select: NM_000384
dbSNP: rs1663984693
Type: Deletion
Location: chr2:21035657 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 248: the vitellogenin domain; a disulfide bond; 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 hypobetalipoproteinemia 1

Similar variants

APOB p.Thr248= Likely benign ★ same residue
APOB c.226_237+1del Pathogenic/Likely pathogenic ★★ same condition
APOB c.78_82+5del Likely pathogenic ★★ same condition
APOB p.Asn1755fs Pathogenic ★★ same condition
APOB p.Asn1772fs Pathogenic/Likely pathogenic ★★ same condition
APOB p.Gly3617fs Pathogenic/Likely pathogenic ★★ same condition
APOB p.His2227fs Pathogenic ★★ same condition
APOB p.Leu1345fs 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-thr248fs (accessed [today's date]).

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