Is APOB p.Pro145Ser (c.433C>T) pathogenic?

APOB p.Pro145Ser (c.433C>T) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-02-19). AlphaMissense: likely benign (0.1837); Common (popmax 12.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Pro145Ser (c.433C>T)?

APOB p.Pro145Ser (c.433C>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

What do computational predictors say about APOB p.Pro145Ser (c.433C>T)?

AlphaMissense predicts likely benign (score 0.1837) — an in-silico prediction, not a clinical call.

APOB p.Pro145Ser

Q: How common is APOB p.Pro145Ser (c.433C>T) in the general population?

APOB p.Pro145Ser (c.433C>T) is common (popmax 12.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.433C>T · rs6752026 · VCV334184

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1837 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.7%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1837	likely benign
REVEL	0.283	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.7% African / African-American · 9,502/74,978 alleles

Filtering AF 12.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.4%

Overall 0.685% 11,050/1,614,088 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.7%	8
Admixed American	1.01%	99
Remaining individualsnot grpmax-eligible	0.955%	105
Middle Eastern	0.693%	144
European (non-Finnish)	0.0234%	4,275
South Asian	0.0231%	4,337
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,868

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.Pro145Ser
Coding: c.433C>T
MANE Select: NM_000384
dbSNP: rs6752026
Type: single nucleotide variant
Location: chr2:21038062 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

APOB p.Pro145= Conflicting classifications of pathogenicity ★ same residue
APOB p.Pro145Ala Uncertain significance ★ ⚠ same residue
APOB p.Pro145Leu 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-pro145ser (accessed [today's date]).

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