Is APOA1 p.Ala178Val (c.533C>T) pathogenic?

APOA1 p.Ala178Val (c.533C>T) is classified Uncertain significance in APOA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-20). AlphaMissense: likely benign (0.0875); Very rare (popmax 0.00017%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with APOA1 p.Ala178Val (c.533C>T)?

APOA1 p.Ala178Val (c.533C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is APOA1 p.Ala178Val (c.533C>T) in the general population?

APOA1 p.Ala178Val (c.533C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about APOA1 p.Ala178Val (c.533C>T)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

APOA1 p.Ala178Val

c.533C>T · VCV3414068

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.2	GERP -2.6
Regional constraint	o/e 1.01	unconstrained · MANE · 1,576 bp · p 0.87 · regional, not allelic
Overall
CADD	6.285	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,177,548 alleles

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

Overall 0.000138% 2/1,452,218 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: APOA1
Protein: p.Ala178Val
Coding: c.533C>T
MANE Select: NM_000039
Type: single nucleotide variant
Location: chr11:116836079 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.66 · 31 PDB
Residue 178: the '10 x approximate tandem repeats' region; a UniProt-annotated variant site (in fha2; no protein expression); a UniProt-annotated variant site (in hdl deficiency; with periorbital xanthelasmas; decreased protein abundance); a UniProt-annotated variant site (in fha2; missing protein expression); an α-helix

Full APOA1 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

Similar variants

APOA1 p.Ala178= Likely benign ★ same residue
APOA1 p.Ala178fs Likely pathogenic ★ same residue
APOA1 p.Ala176Thr Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala176Val Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala204Val Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala218Thr Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala256Thr Uncertain significance ★★ ⚠ same condition
APOA1 p.Arg140Leu 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/apoa1-p-ala178val (accessed [today's date]).

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