Is APP c.1963+8A>C pathogenic?

APP c.1963+8A>C is classified Likely benign in APP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-05-08). Ultra-rare (popmax 0.0165%, mid); Associated with APP-related disorder.

What condition is associated with APP c.1963+8A>C?

APP c.1963+8A>C is associated with APP-related disorder (ClinVar).

How common is APP c.1963+8A>C in the general population?

APP c.1963+8A>C is ultra-rare (popmax 0.0165%, mid) (gnomAD).

APP c.1963+8A>C

rs2517062578 · VCV3036130

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

APP-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +8	near-intronic (+8 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.24	GERP -3.5
Non-coding constraint	Z 0.90	1 kb window · o/e 0.92 · regional · uncalibrated
Overall
CADD	0.527	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00205% 30/1,460,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.0022%	45,357
South Asian	0.0022%	45,466
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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: APP
Coding: c.1963+8A>C
MANE Select: NM_000484
dbSNP: rs2517062578
Type: single nucleotide variant
Location: chr21:25905016 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB

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

Disease context

APP-related disorder

Similar variants

APP p.Leu723Pro Likely pathogenic ★ same condition
APP p.Arg268Thr Uncertain significance ★ ⚠ same condition
APP p.Glu605Gln Uncertain significance ★ ⚠ same condition
APP p.His677Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
APP p.Ile63Val Uncertain significance ★ ⚠ same condition
APP p.Thr276Ala Uncertain significance ★ ⚠ same condition
APP p.Val715Ala Pathogenic ⚠ same condition
APP p.Ala479Ser 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/app-c-1963-plus-8a-c (accessed [today's date]).

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