Is APP p.Arg359Ter (c.1075C>T) pathogenic?

APP p.Arg359Ter (c.1075C>T) is classified Uncertain significance in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-16). Ultra-rare (popmax 0.0183%, amr).

How common is APP p.Arg359Ter (c.1075C>T) in the general population?

APP p.Arg359Ter (c.1075C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

APP p.Arg359Ter

c.1075C>T · VCV4847190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 8 of 18
REVEL	0.353	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/60,016 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00155% 25/1,613,874 alleles · ultra-rare exomes 25/1,461,650 · genomes 0/152,224 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,456
Middle Eastern	0.0165%	6,062
African / African-American	0.00133%	75,022
European (non-Finnish)	0.00102%	98,317

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.Arg359Ter
Coding: c.1075C>T
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:25997375 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB

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

Similar variants

APP p.Arg359Gln Uncertain significance ★ ⚠ same residue
APP p.Arg359Pro Uncertain significance ★ ⚠ same residue
APP p.Ala713Thr Likely pathogenic ★★ ⚠ same type
APP p.Asp694Asn Pathogenic ★★ ⚠ same type
APP p.Glu693Gln Pathogenic ★★ ⚠ same type
APP p.Ile716Phe Pathogenic ★★ ⚠ same type
APP p.Thr714Ala Pathogenic ★★ ⚠ same type
APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ same type

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-arg359ter (accessed [today's date]).

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