Is ABCA1 p.Arg587fs (c.1758dup) pathogenic?

ABCA1 p.Arg587fs (c.1758dup) is classified Pathogenic in ABCA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). Very rare (popmax 0.000424%, nfe).

How common is ABCA1 p.Arg587fs (c.1758dup) in the general population?

ABCA1 p.Arg587fs (c.1758dup) is very rare (popmax 0.000424%, nfe) (gnomAD).

ABCA1 p.Arg587fs

c.1758dup · VCV4709686

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 50
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.6	GERP 1.2, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,662 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,610,890 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,412
European (non-Finnish)grpmax	0.000424%	235,933

Remaining individuals 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: ABCA1
Protein: p.Arg587fs
Coding: c.1758dup
MANE Select: NM_005502
Type: Duplication
Location: chr9:104831058 (GRCh38)
Gene constraint: LOEUF 0.563 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.50 · 7 PDB
Residue 587: an α-helix; the 'gateway domain' region; a UniProt-annotated variant site (in tgd)

Full ABCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA1 p.Arg587Trp Pathogenic/Likely pathogenic ★★ same residue
ABCA1 c.303-42_303-5dup Benign/Likely benign ★★ same type
ABCA1 c.3104-5dup Benign/Likely benign ★★ same type
ABCA1 c.5383-20_5383-17dup Benign ★★ same type
ABCA1 c.5383-20_5383-18dup Benign/Likely benign ★★ same type
ABCA1 c.5383-20_5383-19dup Benign/Likely benign ★★ same type
ABCA1 c.5383-20dup Benign/Likely benign ★★ same type
ABCA1 c.814-14dup Benign ★★ same type

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/abca1-p-arg587fs (accessed [today's date]).

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