Is APOB p.Pro145= (c.435G>A) pathogenic?

APOB p.Pro145= (c.435G>A) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-01). Ultra-rare (popmax 0.0164%, mid); Associated with familial hypobetalipoproteinemia 1.

What condition is associated with APOB p.Pro145= (c.435G>A)?

APOB p.Pro145= (c.435G>A) is associated with familial hypobetalipoproteinemia 1, hypercholesterolemia, autosomal dominant, type B (ClinVar).

How common is APOB p.Pro145= (c.435G>A) in the general population?

APOB p.Pro145= (c.435G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

APOB p.Pro145=

c.435G>A · rs576323709 · VCV898939

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

familial hypobetalipoproteinemia 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.5	GERP -3.5
Overall
CADD	9.027	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.0026% 42/1,614,020 alleles · ultra-rare exomes 39/1,461,868 · genomes 3/152,152 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.004%	24,971
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00333%	30,002
European (non-Finnish)	0.00263%	38,065
East Asian	0.00223%	44,888
South Asian	0.0022%	45,540
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Pro145=
Coding: c.435G>A
MANE Select: NM_000384
dbSNP: rs576323709
Type: single nucleotide variant
Location: chr2:21038060 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 145: the vitellogenin domain; a UniProt-annotated variant site (in)

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

Disease context

familial hypobetalipoproteinemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, autosomal dominant, type B

Similar variants

APOB p.Pro145Ala Uncertain significance ★ ⚠ same residue
APOB p.Pro145Leu Conflicting classifications of pathogenicity ★ same residue
APOB p.Pro145Ser Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro145 (accessed [today's date]).

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