Is ABCA7 p.Leu396fs (c.1186_1196del) pathogenic?

ABCA7 p.Leu396fs (c.11861196del) is classified Conflicting classifications of pathogenicity in ABCA7 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-31). Rare (popmax 0.481%, afr); Associated with neuromuscular disease.

What condition is associated with ABCA7 p.Leu396fs (c.1186_1196del)?

ABCA7 p.Leu396fs (c.1186_1196del) is associated with neuromuscular disease, Alzheimer disease 9 (ClinVar).

How common is ABCA7 p.Leu396fs (c.1186_1196del) in the general population?

ABCA7 p.Leu396fs (c.1186_1196del) is rare (popmax 0.481%, afr) (gnomAD).

ABCA7 p.Leu396fs

c.1186_1196del · rs567222111 · VCV710668

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.481%, afr)

Conditions

neuromuscular disease

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 11 of 47
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.6	GERP -1.2, phastCons 1
Overall
CADD	33.0	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 0.481% African / African-American · 361/75,040 alleles

Filtering AF 0.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.424%

Overall 0.0246% 396/1,611,990 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.481%	208
Admixed American	0.0267%	3,746
Remaining individualsnot grpmax-eligible	0.0192%	5,202
Middle Eastern	0.0168%	5,936
South Asian	0.0033%	30,337
European (non-Finnish)	0.000254%	393,263

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.Leu396fs
Coding: c.1186_1196del
MANE Select: NM_019112
dbSNP: rs567222111
Type: Deletion
Location: chr19:1044709 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.77 · 6 PDB
Residue 396: an α-helix

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

Disease context

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

Also linked: Alzheimer disease 9

Similar variants

ABCA7 p.Glu572fs Likely pathogenic ★ same condition
ABCA7 p.Thr849fs Pathogenic ★ same condition
ABCA7 p.Leu396Arg Uncertain significance ★ ⚠ same residue
ABCA7 p.Pro1367fs 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

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-leu396fs (accessed [today's date]).

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