Is APOB p.Ala1393Val (c.4178C>T) pathogenic?

APOB p.Ala1393Val (c.4178C>T) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-31). AlphaMissense: ambiguous (0.3535); Rare (popmax 0.211%, afr); Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Ala1393Val (c.4178C>T)?

APOB p.Ala1393Val (c.4178C>T) is associated with Cardiovascular phenotype, hypercholesterolemia, familial, 1, hypercholesterolemia, autosomal dominant, type B (ClinVar).

How common is APOB p.Ala1393Val (c.4178C>T) in the general population?

APOB p.Ala1393Val (c.4178C>T) is rare (popmax 0.211%, afr) (gnomAD).

What do computational predictors say about APOB p.Ala1393Val (c.4178C>T)?

AlphaMissense predicts ambiguous (score 0.3535) — an in-silico prediction, not a clinical call.

APOB p.Ala1393Val

c.4178C>T · rs143282164 · VCV218446

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3535 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.211%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3535	ambiguous
REVEL	0.127	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	25.2	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 0.211% African / African-American · 158/75,058 alleles

Filtering AF 0.184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.173%

Overall 0.0152% 245/1,614,148 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.211%	475
Middle Eastern	0.0496%	2,017
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
Remaining individualsnot grpmax-eligible	0.0384%	2,604
Admixed American	0.0167%	6,002
European (non-Finnish)	0.00322%	31,053

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.Ala1393Val
Coding: c.4178C>T
MANE Select: NM_000384
dbSNP: rs143282164
Type: single nucleotide variant
Location: chr2:21013198 (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, familial, 1 hypercholesterolemia, autosomal dominant, type B familial hypobetalipoproteinemia 1

Similar variants

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
APOB p.Arg2520Ter Pathogenic/Likely 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-ala1393val (accessed [today's date]).

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