Is ABCA7 p.Pro2129fs (c.6377_6383dup) pathogenic?

ABCA7 p.Pro2129fs (c.63776383dup) is classified Uncertain significance in ABCA7 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-28). Very rare (popmax 0.00533%, afr); Associated with Alzheimer disease 9.

What condition is associated with ABCA7 p.Pro2129fs (c.6377_6383dup)?

ABCA7 p.Pro2129fs (c.6377_6383dup) is associated with Alzheimer disease 9 (ClinVar).

How common is ABCA7 p.Pro2129fs (c.6377_6383dup) in the general population?

ABCA7 p.Pro2129fs (c.6377_6383dup) is very rare (popmax 0.00533%, afr) (gnomAD).

ABCA7 p.Pro2129fs

c.6377_6383dup · rs2042981462 · VCV1334015

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Conditions

Alzheimer disease 9

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 (47 of 47) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.45	GERP -2.4

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00533% African / African-American · 4/75,056 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000274% 4/1,461,334 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: ABCA7
Protein: p.Pro2129fs
Coding: c.6377_6383dup
MANE Select: NM_019112
dbSNP: rs2042981462
Type: Duplication
Location: chr19:1065360 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.77 · 6 PDB
Residue 2129: the 'disordered' region

Full ABCA7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Alzheimer disease 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCA7 p.Asp1389delinsProValTer Likely pathogenic ★ same condition
ABCA7 p.Pro1246fs Likely pathogenic ★ same condition
ABCA7 p.Glu1728fs Uncertain significance same condition
ABCA7 p.Arg880Trp Uncertain significance ★★ ⚠ same condition
ABCA7 p.Asp2085Asn Uncertain significance ★★ ⚠ same condition
ABCA7 p.Lys1521Gln Uncertain significance ★★ ⚠ same condition
ABCA7 p.Met354Thr Benign/Likely benign ★★ same condition
ABCA7 p.Ser1629Leu Benign/Likely benign ★★ 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/abca7-p-pro2129fs (accessed [today's date]).

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