Is APP p.Phe435= (c.1305C>T) pathogenic?

APP p.Phe435= (c.1305C>T) is classified Benign/Likely benign in APP (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-14). Rare (popmax 0.165%, mid); Associated with Alzheimer disease.

What condition is associated with APP p.Phe435= (c.1305C>T)?

APP p.Phe435= (c.1305C>T) is associated with Alzheimer disease (ClinVar).

How common is APP p.Phe435= (c.1305C>T) in the general population?

APP p.Phe435= (c.1305C>T) is rare (popmax 0.165%, mid) (gnomAD).

APP p.Phe435=

c.1305C>T · rs148180403 · VCV446854

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Conditions

Alzheimer disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.208	benign-leaning
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 8.7	GERP 1.9, phastCons 1
Overall
CADD	16.38	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.165% Middle Eastern · 10/6,062 alleles

Filtering AF 0.0895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0839%

Overall 0.0743% 1,200/1,614,096 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	606
European (non-Finnish)	0.0902%	1,109
Remaining individualsnot grpmax-eligible	0.0816%	1,226
Admixed American	0.06%	1,667
South Asian	0.0198%	5,060
African / African-American	0.0187%	5,360
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,868
Finnishnot grpmax-eligible	0.00625%	16,003

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.Phe435=
Coding: c.1305C>T
MANE Select: NM_000484
dbSNP: rs148180403
Type: single nucleotide variant
Location: chr21:25975223 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 435: the e2 domain; an α-helix

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.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
APP p.Val717Phe 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-phe435 (accessed [today's date]).

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