Is ABCA7 p.Arg1976Ser (c.5926C>A) pathogenic?

ABCA7 p.Arg1976Ser (c.5926C>A) is classified Uncertain significance in ABCA7 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-06-24). AlphaMissense: ambiguous (0.5164); Very rare (popmax 0.00157%, nfe); Associated with Alzheimer disease 9.

What condition is associated with ABCA7 p.Arg1976Ser (c.5926C>A)?

ABCA7 p.Arg1976Ser (c.5926C>A) is associated with Alzheimer disease 9 (ClinVar).

How common is ABCA7 p.Arg1976Ser (c.5926C>A) in the general population?

ABCA7 p.Arg1976Ser (c.5926C>A) is very rare (popmax 0.00157%, nfe) (gnomAD).

What do computational predictors say about ABCA7 p.Arg1976Ser (c.5926C>A)?

AlphaMissense predicts ambiguous (score 0.5164) — an in-silico prediction, not a clinical call.

ABCA7 p.Arg1976Ser

c.5926C>A · rs906507214 · VCV1334014

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00157%, nfe)

Conditions

Alzheimer disease 9

Computational evidence

Protein change
AlphaMissense	0.5164	ambiguous
REVEL	0.628	indeterminate
SaProt	LLR -13.19	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.68	GERP -2.5
Regional constraint	o/e 1.14	unconstrained · MANE · 24 kb · p 5.6e-14 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00157% European (non-Finnish) · 18/1,143,992 alleles

Filtering AF 0.000983% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000811%

Overall 0.0013% 20/1,540,662 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0019%	52,716
Remaining individualsnot grpmax-eligible	0.00167%	59,806
European (non-Finnish)grpmax	0.00157%	63,555

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: ABCA7
Protein: p.Arg1976Ser
Coding: c.5926C>A
MANE Select: NM_019112
dbSNP: rs906507214
Type: single nucleotide variant
Location: chr19:1063838 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.77 · 6 PDB
Residue 1976: the abc transporter 2 domain

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.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
ABCA7 c.3423+1G>T Likely pathogenic ★ same condition
ABCA7 c.67-1G>A Pathogenic ★ same condition
ABCA7 p.Gln1183Ter Likely pathogenic ★ 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-arg1976ser (accessed [today's date]).

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