Is APOB p.Gln845His (c.2535G>C) pathogenic?

APOB p.Gln845His (c.2535G>C) is classified Uncertain significance in APOB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-24). AlphaMissense: ambiguous (0.3695); Ultra-rare (popmax 0.0143%, sas); Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Gln845His (c.2535G>C)?

APOB p.Gln845His (c.2535G>C) is associated with Cardiovascular phenotype, hypercholesterolemia, autosomal dominant, type B, familial hypobetalipoproteinemia 1 (ClinVar).

How common is APOB p.Gln845His (c.2535G>C) in the general population?

APOB p.Gln845His (c.2535G>C) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about APOB p.Gln845His (c.2535G>C)?

AlphaMissense predicts ambiguous (score 0.3695) — an in-silico prediction, not a clinical call.

APOB p.Gln845His

c.2535G>C · rs778467805 · VCV630336

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3695	ambiguous
REVEL	0.191	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.1	GERP -3.1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	16.59	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 0.0143% South Asian · 13/91,090 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.000889% 13/1,461,872 alleles · ultra-rare

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.Gln845His
Coding: c.2535G>C
MANE Select: NM_000384
dbSNP: rs778467805
Type: single nucleotide variant
Location: chr2:21023594 (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.Gln845Arg 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
APOB p.Arg2513Ter 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-gln845his (accessed [today's date]).

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