Is APOA1 p.Ala178fs (c.532_533del) pathogenic?

APOA1 p.Ala178fs (c.532533del) is classified Likely pathogenic in APOA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-30). Very rare (popmax 0.000509%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with APOA1 p.Ala178fs (c.532_533del)?

APOA1 p.Ala178fs (c.532_533del) is associated with Cardiovascular phenotype (ClinVar).

How common is APOA1 p.Ala178fs (c.532_533del) in the general population?

APOA1 p.Ala178fs (c.532_533del) is very rare (popmax 0.000509%, nfe) (gnomAD).

APOA1 p.Ala178fs

c.532_533del · rs781350389 · VCV3127886

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.32	GERP -1.4

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,178,264 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000482% 7/1,453,692 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00171%	58,574
European (non-Finnish)grpmax	0.000509%	196,377

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala178fs
Coding: c.532_533del
MANE Select: NM_000039
dbSNP: rs781350389
Type: Microsatellite
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.Ala178Val Uncertain significance ★ ⚠ same residue
APOA1 p.Ala178= Likely benign ★ same residue
APOA1 p.Ala178_His179insArgAlaArgAla Uncertain significance 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

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-ala178fs (accessed [today's date]).

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