Is APOB p.Gln4122Lys (c.12364C>A) pathogenic?

APOB p.Gln4122Lys (c.12364C>A) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-08-04). AlphaMissense: likely benign (0.0763); Ultra-rare (popmax 0.0123%, afr); Associated with hypercholesterolemia, autosomal dominant, type B.

What condition is associated with APOB p.Gln4122Lys (c.12364C>A)?

APOB p.Gln4122Lys (c.12364C>A) is associated with hypercholesterolemia, autosomal dominant, type B, familial hypercholesterolemia, familial hypobetalipoproteinemia 1 (ClinVar).

How common is APOB p.Gln4122Lys (c.12364C>A) in the general population?

APOB p.Gln4122Lys (c.12364C>A) is ultra-rare (popmax 0.0123%, afr) (gnomAD).

What do computational predictors say about APOB p.Gln4122Lys (c.12364C>A)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

APOB p.Gln4122Lys

c.12364C>A · rs767603929 · VCV630240

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hypercholesterolemia, autosomal dominant, type B

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.067	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 2.9	GERP -0.21, phastCons 0.24
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	5.059	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 0.0123% African / African-American · 9/73,312 alleles

Filtering AF 0.00636% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00477%

Overall 0.0014% 22/1,570,470 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0123%	8,146
Admixed American	0.00741%	13,501
Remaining individualsnot grpmax-eligible	0.00331%	30,211
European (non-Finnish)	0.000604%	165,569

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.Gln4122Lys
Coding: c.12364C>A
MANE Select: NM_000384
dbSNP: rs767603929
Type: single nucleotide variant
Location: chr2:21003058 (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 hypercholesterolemia 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-gln4122lys (accessed [today's date]).

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