Is APOB p.Asp1381Glu (c.4143C>A) pathogenic?

APOB p.Asp1381Glu (c.4143C>A) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1263); Rare (popmax 0.203%, eas); Associated with hypercholesterolemia, autosomal dominant, type B.

How common is APOB p.Asp1381Glu (c.4143C>A) in the general population?

APOB p.Asp1381Glu (c.4143C>A) is rare (popmax 0.203%, eas) (gnomAD).

What do computational predictors say about APOB p.Asp1381Glu (c.4143C>A)?

AlphaMissense predicts likely benign (score 0.1263) — an in-silico prediction, not a clinical call.

APOB p.Asp1381Glu

Q: What condition is associated with APOB p.Asp1381Glu (c.4143C>A)?

APOB p.Asp1381Glu (c.4143C>A) is associated with hypercholesterolemia, autosomal dominant, type B, familial hypobetalipoproteinemia 1 (ClinVar).

c.4143C>A · rs754597311 · VCV334147

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1263 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.203%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hypercholesterolemia, autosomal dominant, type B

Computational evidence

Protein change
AlphaMissense	0.1263	likely benign
REVEL	0.058	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22	GERP -3.4, phastCons 0.002
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	8.502	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 0.203% East Asian · 91/44,870 alleles

Filtering AF 0.169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.157%

Overall 0.0057% 92/1,614,190 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.203%	493
Admixed American	0.00167%	60,024

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.Asp1381Glu
Coding: c.4143C>A
MANE Select: NM_000384
dbSNP: rs754597311
Type: single nucleotide variant
Location: chr2:21013233 (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

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.Asp1381= Likely benign ★ same residue
APOB p.Asp1381Tyr 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

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-asp1381glu (accessed [today's date]).

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