Is APOB p.Arg3989Cys (c.11965C>T) pathogenic?

APOB p.Arg3989Cys (c.11965C>T) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-05-07). AlphaMissense: likely benign (0.0923); Ultra-rare (popmax 0.0293%, afr); Associated with familial hypercholesterolemia.

What condition is associated with APOB p.Arg3989Cys (c.11965C>T)?

APOB p.Arg3989Cys (c.11965C>T) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1, hypercholesterolemia, autosomal dominant, type B (ClinVar).

How common is APOB p.Arg3989Cys (c.11965C>T) in the general population?

APOB p.Arg3989Cys (c.11965C>T) is ultra-rare (popmax 0.0293%, afr) (gnomAD).

What do computational predictors say about APOB p.Arg3989Cys (c.11965C>T)?

AlphaMissense predicts likely benign (score 0.0923) — an in-silico prediction, not a clinical call.

APOB p.Arg3989Cys

c.11965C>T · rs150713761 · VCV369878

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0923 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.0923	likely benign
REVEL	0.071	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 -0.14	GERP -1.4
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	18.63	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 0.0293% African / African-American · 22/75,022 alleles

Filtering AF 0.0198% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00353% 57/1,614,012 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0293%	3,410
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0032%	31,252
European (non-Finnish)	0.00254%	39,331
South Asian	0.0022%	45,531

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.Arg3989Cys
Coding: c.11965C>T
MANE Select: NM_000384
dbSNP: rs150713761
Type: single nucleotide variant
Location: chr2:21004391 (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

familial hypercholesterolemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

APOB p.Arg3989His Conflicting classifications of pathogenicity ★ ⚠ same residue
APOB p.Arg3989Ser Uncertain significance ★ 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-arg3989cys (accessed [today's date]).

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