Is APOB p.Pro1902Leu (c.5705C>T) pathogenic?

APOB p.Pro1902Leu (c.5705C>T) is classified Uncertain significance in APOB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-24). AlphaMissense: ambiguous (0.5108); Ultra-rare (popmax 0.0117%, amr); Associated with APOB-related disorder.

What condition is associated with APOB p.Pro1902Leu (c.5705C>T)?

APOB p.Pro1902Leu (c.5705C>T) is associated with APOB-related disorder, hypercholesterolemia, autosomal dominant, type B, familial hypobetalipoproteinemia 1 (ClinVar).

How common is APOB p.Pro1902Leu (c.5705C>T) in the general population?

APOB p.Pro1902Leu (c.5705C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about APOB p.Pro1902Leu (c.5705C>T)?

AlphaMissense predicts ambiguous (score 0.5108) — an in-silico prediction, not a clinical call.

APOB p.Pro1902Leu

c.5705C>T · rs368848646 · VCV1000350

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5108 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

APOB-related disorder

Computational evidence

Protein change
AlphaMissense	0.5108	ambiguous
REVEL	0.434	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	26.3	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 0.0117% Admixed American · 7/59,996 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000743% 12/1,614,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,571
African / African-American	0.00534%	18,730
European (non-Finnish)	8.47e-05%	1,180,026

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.Pro1902Leu
Coding: c.5705C>T
MANE Select: NM_000384
dbSNP: rs368848646
Type: single nucleotide variant
Location: chr2:21011163 (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

APOB-related disorder

Also linked: hypercholesterolemia, autosomal dominant, type B familial hypobetalipoproteinemia 1

Similar variants

APOB p.Pro1902= Likely benign ★★ 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-pro1902leu (accessed [today's date]).

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