Is APP p.Phe179Ser (c.536T>C) pathogenic?

APP p.Phe179Ser (c.536T>C) is classified Uncertain significance in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: likely pathogenic (0.9981); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with APP p.Phe179Ser (c.536T>C)?

APP p.Phe179Ser (c.536T>C) is associated with Inborn genetic diseases (ClinVar).

How common is APP p.Phe179Ser (c.536T>C) in the general population?

APP p.Phe179Ser (c.536T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APP p.Phe179Ser (c.536T>C)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

APP p.Phe179Ser

c.536T>C · VCV3886942

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic · top 4% in APP
REVEL	0.985	strongly pathogenic-leaning
SaProt	LLR -15.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APP
Protein: p.Phe179Ser
Coding: c.536T>C
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:26051126 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 179: the e1 domain; a β-strand; the 'cubd subdomain' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APP p.Arg747His Uncertain significance ★★ ⚠ same condition
APP p.Asp560Asn Uncertain significance ★★ ⚠ same condition
APP p.Ile666Phe Uncertain significance ★★ ⚠ same condition
APP p.Leu5Val Uncertain significance ★★ ⚠ same condition
APP p.Ala339Gly Uncertain significance ★ same condition
APP p.Ala358Ser Uncertain significance ★ ⚠ same condition
APP p.Ala416Val Uncertain significance ★ ⚠ same condition
APP p.Arg306His Conflicting classifications of pathogenicity ★ ⚠ 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-phe179ser (accessed [today's date]).

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