Is APP p.Arg470His (c.1409G>A) pathogenic?

APP p.Arg470His (c.1409G>A) is classified Uncertain significance in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-13). AlphaMissense: likely pathogenic (0.5919); Ultra-rare (popmax 0.0165%, mid); Associated with cerebral amyloid angiopathy, APP-related.

What condition is associated with APP p.Arg470His (c.1409G>A)?

APP p.Arg470His (c.1409G>A) is associated with cerebral amyloid angiopathy, APP-related (ClinVar).

How common is APP p.Arg470His (c.1409G>A) in the general population?

APP p.Arg470His (c.1409G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Hereditary cerebral amyloid angiopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about APP p.Arg470His (c.1409G>A)?

AlphaMissense predicts likely pathogenic (score 0.5919) — an in-silico prediction, not a clinical call.

APP p.Arg470His

c.1409G>A · rs182162117 · VCV1299705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5919 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cerebral amyloid angiopathy, APP-related

Computational evidence

Protein change
AlphaMissense	0.5919	likely pathogenic
REVEL	0.47	indeterminate
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	32.0	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00062% 10/1,614,002 alleles · ultra-rare exomes 7/1,461,862 · genomes 3/152,140 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Finnishnot grpmax-eligible	0.00312%	32,010
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000424%	236,000

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
Protein: p.Arg470His
Coding: c.1409G>A
MANE Select: NM_000484
dbSNP: rs182162117
Type: single nucleotide variant
Location: chr21:25975119 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 470: the e2 domain; an α-helix

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

Disease context

cerebral amyloid angiopathy, APP-related — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary cerebral amyloid angiopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

APP p.Ala713Thr Likely pathogenic ★★ ⚠ same condition
APP p.Asp694Asn Pathogenic ★★ ⚠ same condition
APP p.Glu693Gln Pathogenic ★★ ⚠ same condition
APP p.Val717Ile Pathogenic ★★ ⚠ same condition
APP p.Arg16Gln Uncertain significance ★★ ⚠ same condition
APP p.Arg585Lys Uncertain significance ★★ ⚠ same condition
APP p.Ser346Tyr Uncertain significance ★★ ⚠ same condition
APP p.Val225Ala 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-arg470his (accessed [today's date]).

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