Is APP p.Ser206Leu (c.617C>T) pathogenic?

APP p.Ser206Leu (c.617C>T) is classified Uncertain significance in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-27). AlphaMissense: likely benign (0.2977); Very rare (popmax 0.00542%, nfe); Associated with Alzheimer disease.

What condition is associated with APP p.Ser206Leu (c.617C>T)?

APP p.Ser206Leu (c.617C>T) is associated with Alzheimer disease (ClinVar).

How common is APP p.Ser206Leu (c.617C>T) in the general population?

APP p.Ser206Leu (c.617C>T) is very rare (popmax 0.00542%, nfe) (gnomAD).

What do computational predictors say about APP p.Ser206Leu (c.617C>T)?

AlphaMissense predicts likely benign (score 0.2977) — an in-silico prediction, not a clinical call.

APP p.Ser206Leu

c.617C>T · VCV3690634

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00542%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.2977	likely benign
REVEL	0.565	indeterminate
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00542% European (non-Finnish) · 64/1,180,040 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.00409% 66/1,613,974 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00542%	18,438
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Ser206Leu
Coding: c.617C>T
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:26051045 (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.Ser206= Conflicting classifications of pathogenicity ★ 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-ser206leu (accessed [today's date]).

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