Is APOB p.Leu3763Pro (c.11288T>C) pathogenic?

APOB p.Leu3763Pro (c.11288T>C) is classified Uncertain significance in APOB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-26). AlphaMissense: likely benign (0.297); Very rare (popmax 8.47e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Leu3763Pro (c.11288T>C)?

APOB p.Leu3763Pro (c.11288T>C) is associated with Cardiovascular phenotype, familial hypercholesterolemia (ClinVar).

How common is APOB p.Leu3763Pro (c.11288T>C) in the general population?

APOB p.Leu3763Pro (c.11288T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about APOB p.Leu3763Pro (c.11288T>C)?

AlphaMissense predicts likely benign (score 0.297) — an in-silico prediction, not a clinical call.

APOB p.Leu3763Pro

c.11288T>C · rs1663106152 · VCV979091

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.297 · ACMG-weighted

gnomAD v4.1

Rare

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

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.297	likely benign
REVEL	0.295	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.6, phastCons 0.98
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,990 alleles

Overall 0.000657% 1/152,184 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.Leu3763Pro
Coding: c.11288T>C
MANE Select: NM_000384
dbSNP: rs1663106152
Type: single nucleotide variant
Location: chr2:21005580 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia

Similar variants

APOB p.Leu3763Val Conflicting classifications of pathogenicity ★ ⚠ same residue
APOB p.Leu3763Ile Likely benign ★ same residue
APOB p.Arg2085Ter Pathogenic/Likely pathogenic ★★ same condition
APOB p.Arg3527Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOB p.Arg3527Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOB p.Arg490Trp Pathogenic/Likely pathogenic ★★ same condition
APOB c.1124+3A>G Uncertain significance ★★ same condition
APOB c.11788+4A>G Uncertain significance ★★ 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-leu3763pro (accessed [today's date]).

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