Is APP p.Ala201= (c.603G>A) pathogenic?

APP p.Ala201= (c.603G>A) is classified Likely benign in APP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-18). Ultra-rare (popmax 0.0164%, mid); Associated with APP-related disorder.

What condition is associated with APP p.Ala201= (c.603G>A)?

APP p.Ala201= (c.603G>A) is associated with APP-related disorder (ClinVar).

How common is APP p.Ala201= (c.603G>A) in the general population?

APP p.Ala201= (c.603G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

APP p.Ala201=

c.603G>A · VCV3354095

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

APP-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.043	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5	GERP -3.7
Overall
CADD	0.919	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000867% 14/1,614,068 alleles · ultra-rare exomes 13/1,461,884 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00891%	11,226
Remaining individualsnot grpmax-eligible	0.0048%	20,830
South Asian	0.0022%	45,543
Finnishnot grpmax-eligible	0.00156%	64,034
African / African-American	0.00133%	74,924
European (non-Finnish)	0.000169%	590,019

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.Ala201=
Coding: c.603G>A
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:26051059 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 201: the 'disordered' region

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

Disease context

APP-related disorder

Similar variants

APP p.Ala201Val Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-ala201 (accessed [today's date]).

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