Is APOB p.Ser3456Phe (c.10367C>T) pathogenic?

APOB p.Ser3456Phe (c.10367C>T) is classified Uncertain significance in APOB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-15). AlphaMissense: ambiguous (0.394); Very rare (popmax 0.000169%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with APOB p.Ser3456Phe (c.10367C>T)?

APOB p.Ser3456Phe (c.10367C>T) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is APOB p.Ser3456Phe (c.10367C>T) in the general population?

APOB p.Ser3456Phe (c.10367C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about APOB p.Ser3456Phe (c.10367C>T)?

AlphaMissense predicts ambiguous (score 0.394) — an in-silico prediction, not a clinical call.

APOB p.Ser3456Phe

c.10367C>T · rs1217782046 · VCV548032

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.394 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.394	ambiguous
REVEL	0.692	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	26.1	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 0.000169% European (non-Finnish) · 2/1,179,974 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,796 alleles · very 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.Ser3456Phe
Coding: c.10367C>T
MANE Select: NM_000384
dbSNP: rs1217782046
Type: single nucleotide variant
Location: chr2:21006501 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 3456: the 'heparin-binding' region

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

Disease context

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

Similar variants

APOB p.Arg3527Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOB p.Arg3527Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOB p.Gln1551Ter Pathogenic ★★ same condition
APOB c.1352+60C>A Uncertain significance ★★ same condition
APOB p.Ala3837Ser Uncertain significance ★★ ⚠ same condition
APOB p.Ala527Val Uncertain significance ★★ ⚠ same condition
APOB p.Arg4385Cys Uncertain significance ★★ ⚠ same condition
APOB p.Asp4390His Uncertain significance ★★ ⚠ 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-ser3456phe (accessed [today's date]).

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