Is APP p.Arg468Cys (c.1402C>T) pathogenic?

APP p.Arg468Cys (c.1402C>T) is classified Likely benign in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-02). AlphaMissense: likely pathogenic (0.7888); Very rare (popmax 0.00401%, afr); Associated with Alzheimer disease.

What condition is associated with APP p.Arg468Cys (c.1402C>T)?

APP p.Arg468Cys (c.1402C>T) is associated with Alzheimer disease (ClinVar).

How common is APP p.Arg468Cys (c.1402C>T) in the general population?

APP p.Arg468Cys (c.1402C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about APP p.Arg468Cys (c.1402C>T)?

AlphaMissense predicts likely pathogenic (score 0.7888) — an in-silico prediction, not a clinical call.

APP p.Arg468Cys

c.1402C>T · rs1162419578 · VCV1413498

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7888 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.7888	likely pathogenic
REVEL	0.699	pathogenic-leaning
SaProt	LLR -15.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	33.0	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 0.00401% African / African-American · 3/74,870 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000805% 13/1,613,942 alleles · very rare exomes 12/1,461,876 · genomes 1/152,066 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,957
Admixed American	0.00167%	59,986
European (non-Finnish)	0.000763%	131,112

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.Arg468Cys
Coding: c.1402C>T
MANE Select: NM_000484
dbSNP: rs1162419578
Type: single nucleotide variant
Location: chr21:25975126 (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.Arg468His Uncertain significance ★ ⚠ 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-arg468cys (accessed [today's date]).

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