Is APOB p.Leu165= (c.495G>C) pathogenic?

APOB p.Leu165= (c.495G>C) is classified Uncertain significance in APOB (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 0.0011%, nfe); Associated with familial hypobetalipoproteinemia 1.

What condition is associated with APOB p.Leu165= (c.495G>C)?

APOB p.Leu165= (c.495G>C) is associated with familial hypobetalipoproteinemia 1, hypercholesterolemia, autosomal dominant, type B (ClinVar).

How common is APOB p.Leu165= (c.495G>C) in the general population?

APOB p.Leu165= (c.495G>C) is very rare (popmax 0.0011%, nfe) (gnomAD).

APOB p.Leu165=

c.495G>C · rs886055595 · VCV334183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

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 1.7	GERP -0.049, phastCons 1
Overall
CADD	8.259	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,180,038 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000889% 13/1,461,888 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.Leu165=
Coding: c.495G>C
MANE Select: NM_000384
dbSNP: rs886055595
Type: single nucleotide variant
Location: chr2:21038000 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 165: the vitellogenin domain

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.Leu165Pro Likely benign ★ same residue
APOB p.Leu165Arg 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-leu165 (accessed [today's date]).

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