Is APOB p.Ser3294Pro (c.9880T>C) pathogenic?

APOB p.Ser3294Pro (c.9880T>C) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1262); Common (popmax 5.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with familial hypobetalipoproteinemia 1.

What condition is associated with APOB p.Ser3294Pro (c.9880T>C)?

APOB p.Ser3294Pro (c.9880T>C) is associated with familial hypobetalipoproteinemia 1, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

What do computational predictors say about APOB p.Ser3294Pro (c.9880T>C)?

AlphaMissense predicts likely benign (score 0.1262) — an in-silico prediction, not a clinical call.

APOB p.Ser3294Pro

Q: How common is APOB p.Ser3294Pro (c.9880T>C) in the general population?

APOB p.Ser3294Pro (c.9880T>C) is common (popmax 5.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.9880T>C · rs12720855 · VCV255990

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.1262 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial hypobetalipoproteinemia 1

Computational evidence

Protein change
AlphaMissense	0.1262	likely benign
REVEL	0.223	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 9.5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	22.1	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 5.3% African / African-American · 3,978/75,014 alleles

Filtering AF 5.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.11%

Overall 0.278% 4,494/1,614,042 alleles · common exomes 2,199/1,461,768 · genomes 2,295/152,274 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.3%	19
Remaining individualsnot grpmax-eligible	0.326%	306
Admixed American	0.325%	308
Middle Eastern	0.281%	356
European (non-Finnish)	0.00788%	12,688
South Asian	0.00769%	13,011

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.Ser3294Pro
Coding: c.9880T>C
MANE Select: NM_000384
dbSNP: rs12720855
Type: single nucleotide variant
Location: chr2:21006988 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 3294: 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: familial hypercholesterolemia hypercholesterolemia, familial, 1 hypercholesterolemia, autosomal dominant, type B

Similar variants

APOB p.Ser3294= Likely benign ★ 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-ser3294pro (accessed [today's date]).

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