Is APP p.Ser206= (c.618G>A) pathogenic?

APP p.Ser206= (c.618G>A) is classified Conflicting classifications of pathogenicity in APP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0557%, eas); Associated with Alzheimer disease.

What condition is associated with APP p.Ser206= (c.618G>A)?

APP p.Ser206= (c.618G>A) is associated with Alzheimer disease (ClinVar).

How common is APP p.Ser206= (c.618G>A) in the general population?

APP p.Ser206= (c.618G>A) is ultra-rare (popmax 0.0557%, eas) (gnomAD).

APP p.Ser206=

c.618G>A · rs201022619 · VCV339643

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0557%, eas)

Conditions

Alzheimer disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.047	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.7
Overall
CADD	0.025	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0557% East Asian · 25/44,880 alleles

Filtering AF 0.0387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00248% 40/1,614,150 alleles · ultra-rare exomes 34/1,461,876 · genomes 6/152,274 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0557%	1,795
African / African-American	0.00267%	37,517
Remaining individualsnot grpmax-eligible	0.0016%	62,508
South Asian	0.0011%	91,078
European (non-Finnish)	0.000932%	107,276

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.Ser206=
Coding: c.618G>A
MANE Select: NM_000484
dbSNP: rs201022619
Type: single nucleotide variant
Location: chr21:26051044 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 206: the 'disordered' region; a modified residue (phosphoserine; by ck1)

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.Ser206Leu 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-ser206 (accessed [today's date]).

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