Is APOB p.Asp1997Glu (c.5991T>A) pathogenic?

APOB p.Asp1997Glu (c.5991T>A) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-12-10). AlphaMissense: likely benign (0.109); Very rare (popmax 0.00475%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Asp1997Glu (c.5991T>A)?

APOB p.Asp1997Glu (c.5991T>A) is associated with Cardiovascular phenotype, hypercholesterolemia, autosomal dominant, type B, familial hypobetalipoproteinemia 1 (ClinVar).

How common is APOB p.Asp1997Glu (c.5991T>A) in the general population?

APOB p.Asp1997Glu (c.5991T>A) is very rare (popmax 0.00475%, nfe) (gnomAD).

What do computational predictors say about APOB p.Asp1997Glu (c.5991T>A)?

AlphaMissense predicts likely benign (score 0.109) — an in-silico prediction, not a clinical call.

APOB p.Asp1997Glu

c.5991T>A · rs768045701 · VCV430496

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.109 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00475%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.109	likely benign
REVEL	0.024	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 0.23	GERP -3.8, phastCons 0.006
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	2.413	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 0.00475% European (non-Finnish) · 56/1,180,028 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.00353% 57/1,614,020 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00475%	21,072
African / African-American	0.00134%	74,906

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.Asp1997Glu
Coding: c.5991T>A
MANE Select: NM_000384
dbSNP: rs768045701
Type: single nucleotide variant
Location: chr2:21010877 (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: hypercholesterolemia, autosomal dominant, type B familial hypobetalipoproteinemia 1

Similar variants

APOB p.Asp1997Asn Likely benign ★★ same residue
APOB p.Asp1997Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
APOB p.Asp1997= 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

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-asp1997glu (accessed [today's date]).

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