Is APOB p.Asp2299His (c.6895G>C) pathogenic?

APOB p.Asp2299His (c.6895G>C) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1005); Low-frequency (popmax 2.45%, afr); Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Asp2299His (c.6895G>C)?

APOB p.Asp2299His (c.6895G>C) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is APOB p.Asp2299His (c.6895G>C) in the general population?

APOB p.Asp2299His (c.6895G>C) is low-frequency (popmax 2.45%, afr) (gnomAD).

What do computational predictors say about APOB p.Asp2299His (c.6895G>C)?

AlphaMissense predicts likely benign (score 0.1005) — an in-silico prediction, not a clinical call.

APOB p.Asp2299His

c.6895G>C · rs12713681 · VCV252485

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1005 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.45%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1005	likely benign
REVEL	0.104	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 0.037	GERP -0.16, phastCons 0.83
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	16.79	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 2.45% African / African-American · 1,840/75,046 alleles

Filtering AF 2.36% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.32%

Overall 0.137% 2,206/1,613,804 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.45%	41
Middle Eastern	0.347%	288
Admixed American	0.192%	522
Remaining individualsnot grpmax-eligible	0.173%	579
European (non-Finnish)	0.00975%	10,260
Finnishnot grpmax-eligible	0.00626%	15,969
South Asian	0.00329%	30,357

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.Asp2299His
Coding: c.6895G>C
MANE Select: NM_000384
dbSNP: rs12713681
Type: single nucleotide variant
Location: chr2:21009973 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2299: a UniProt-annotated variant site (in)

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 hypercholesterolemia, familial, 1 hypercholesterolemia, autosomal dominant, type B familial hypobetalipoproteinemia 1

Similar variants

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
APOB p.Arg2520Ter 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-asp2299his (accessed [today's date]).

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