Is APP p.Ala479Ser (c.1435G>T) pathogenic?

APP p.Ala479Ser (c.1435G>T) is classified Uncertain significance in APP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-25). AlphaMissense: likely benign (0.1645); Ultra-rare (popmax 0.0122%, nfe); Associated with APP-related disorder.

What condition is associated with APP p.Ala479Ser (c.1435G>T)?

APP p.Ala479Ser (c.1435G>T) is associated with APP-related disorder (ClinVar).

How common is APP p.Ala479Ser (c.1435G>T) in the general population?

APP p.Ala479Ser (c.1435G>T) is ultra-rare (popmax 0.0122%, nfe) (gnomAD).

What do computational predictors say about APP p.Ala479Ser (c.1435G>T)?

AlphaMissense predicts likely benign (score 0.1645) — an in-silico prediction, not a clinical call.

APP p.Ala479Ser

c.1435G>T · VCV3351879

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1645 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

APP-related disorder

Computational evidence

Protein change
AlphaMissense	0.1645	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -5.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	23.6	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 0.0122% European (non-Finnish) · 144/1,180,018 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00994%

Overall 0.00911% 147/1,613,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0122%	8,195
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00134%	74,894

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.Ala479Ser
Coding: c.1435G>T
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:25975093 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 479: the e2 domain; an α-helix

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

Disease context

APP-related disorder

Similar variants

APP p.Ala479Thr Uncertain significance ★ 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-ala479ser (accessed [today's date]).

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