Is APP p.Arg468His (c.1403G>A) pathogenic?

APP p.Arg468His (c.1403G>A) is classified Uncertain significance in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: likely benign (0.3066); Very rare (popmax 0.0011%, sas); Associated with Alzheimer disease.

What condition is associated with APP p.Arg468His (c.1403G>A)?

APP p.Arg468His (c.1403G>A) is associated with Alzheimer disease (ClinVar).

How common is APP p.Arg468His (c.1403G>A) in the general population?

APP p.Arg468His (c.1403G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about APP p.Arg468His (c.1403G>A)?

AlphaMissense predicts likely benign (score 0.3066) — an in-silico prediction, not a clinical call.

APP p.Arg468His

c.1403G>A · VCV4777577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3066 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.3066	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -10.67	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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 0.0011% South Asian · 1/91,074 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000558% 9/1,613,918 alleles · very rare exomes 8/1,461,864 · genomes 1/152,054 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,008
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	0.000508%	196,668

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: APP
Protein: p.Arg468His
Coding: c.1403G>A
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:25975125 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 468: the e2 domain; an α-helix

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

Disease context

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

Similar variants

APP p.Arg468Cys Likely benign ★ same residue
APP p.Ala713Thr Likely pathogenic ★★ ⚠ same condition
APP p.Asp694Asn Pathogenic ★★ ⚠ same condition
APP p.Glu693Gln Pathogenic ★★ ⚠ same condition
APP p.Ile716Phe Pathogenic ★★ ⚠ same condition
APP p.Thr714Ala Pathogenic ★★ ⚠ same condition
APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
APP p.Val717Ile 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/app-p-arg468his (accessed [today's date]).

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