Is APOB p.Leu3469Pro (c.10406T>C) pathogenic?

APOB p.Leu3469Pro (c.10406T>C) is classified Uncertain significance in APOB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-24). AlphaMissense: likely benign (0.1503); Absent from gnomAD v4.1; Associated with familial hypercholesterolemia.

What condition is associated with APOB p.Leu3469Pro (c.10406T>C)?

APOB p.Leu3469Pro (c.10406T>C) is associated with familial hypercholesterolemia (ClinVar).

How common is APOB p.Leu3469Pro (c.10406T>C) in the general population?

APOB p.Leu3469Pro (c.10406T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APOB p.Leu3469Pro (c.10406T>C)?

AlphaMissense predicts likely benign (score 0.1503) — an in-silico prediction, not a clinical call.

APOB p.Leu3469Pro

c.10406T>C · VCV4086260

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1503 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.1503	likely benign
REVEL	0.409	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 0.96
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	18.05	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APOB
Protein: p.Leu3469Pro
Coding: c.10406T>C
MANE Select: NM_000384
Type: single nucleotide variant
Location: chr2:21006462 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 3469: the 'heparin-binding' region

Full APOB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

APOB p.Leu3469= 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.Ala1695Val Uncertain significance ★★ ⚠ same condition
APOB p.Ala68Thr Uncertain significance ★★ ⚠ same condition
APOB p.Arg3183Gly Uncertain significance ★★ ⚠ same condition
APOB p.Arg3311Ile 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-leu3469pro (accessed [today's date]).

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