Is APP p.Ile63Val (c.187A>G) pathogenic?

APP p.Ile63Val (c.187A>G) is classified Uncertain significance in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-14). AlphaMissense: likely benign (0.0758); Absent from gnomAD v4.1; Associated with APP-related disorder.

What condition is associated with APP p.Ile63Val (c.187A>G)?

APP p.Ile63Val (c.187A>G) is associated with APP-related disorder (ClinVar).

How common is APP p.Ile63Val (c.187A>G) in the general population?

APP p.Ile63Val (c.187A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APP p.Ile63Val (c.187A>G)?

AlphaMissense predicts likely benign (score 0.0758) — an in-silico prediction, not a clinical call.

APP p.Ile63Val

c.187A>G · rs779329120 · VCV2630138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0758 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

APP-related disorder

Computational evidence

Protein change
AlphaMissense	0.0758	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.054, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APP
Protein: p.Ile63Val
Coding: c.187A>G
MANE Select: NM_000484
dbSNP: rs779329120
Type: single nucleotide variant
Location: chr21:26112017 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 63: the e1 domain; the 'gfld subdomain' region

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.Thr276Ala Uncertain significance ★ ⚠ same condition
APP p.Val715Ala Pathogenic ⚠ same condition
APP p.Ala479Ser Uncertain significance ⚠ same condition
APP p.Arg397Thr 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-p-ile63val (accessed [today's date]).

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