Is APOB p.Arg1128His (c.3383G>A) pathogenic?

APOB p.Arg1128His (c.3383G>A) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 20 submitters; last evaluated 2026-08-05). AlphaMissense: likely benign (0.0734); Rare (popmax 0.643%, mid); Associated with APOB-related disorder.

What condition is associated with APOB p.Arg1128His (c.3383G>A)?

APOB p.Arg1128His (c.3383G>A) is associated with APOB-related disorder, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is APOB p.Arg1128His (c.3383G>A) in the general population?

APOB p.Arg1128His (c.3383G>A) is rare (popmax 0.643%, mid) (gnomAD).

What do computational predictors say about APOB p.Arg1128His (c.3383G>A)?

AlphaMissense predicts likely benign (score 0.0734) — an in-silico prediction, not a clinical call.

APOB p.Arg1128His

c.3383G>A · rs12713843 · VCV281142

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 20 submitters

AlphaMissense

likely benign

0.0734 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.643%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

APOB-related disorder

Computational evidence

Protein change
AlphaMissense	0.0734	likely benign
REVEL	0.184	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.39	GERP -1.2
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	21.1	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 0.643% Middle Eastern · 39/6,062 alleles

Filtering AF 0.573% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.556%

Overall 0.455% 7,337/1,614,006 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.643%	155
South Asian	0.615%	163
Remaining individualsnot grpmax-eligible	0.507%	197
European (non-Finnish)	0.507%	197
Admixed American	0.388%	258
Finnishnot grpmax-eligible	0.224%	447
African / African-American	0.0813%	1,230
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
East Asian	0.00669%	14,957

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.Arg1128His
Coding: c.3383G>A
MANE Select: NM_000384
dbSNP: rs12713843
Type: single nucleotide variant
Location: chr2:21015495 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1128: a UniProt-annotated variant site (in)

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

Disease context

APOB-related disorder

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

Similar variants

APOB p.Arg1128Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
APOB p.Arg1128= 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-arg1128his (accessed [today's date]).

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