Is APP p.Arg16= (c.48G>T) pathogenic?

APP p.Arg16= (c.48G>T) is classified Likely benign in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-31). Ultra-rare (popmax 0.0238%, sas).

How common is APP p.Arg16= (c.48G>T) in the general population?

APP p.Arg16= (c.48G>T) is ultra-rare (popmax 0.0238%, sas) (gnomAD).

APP p.Arg16=

c.48G>T · VCV4847224

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0238%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.92, phastCons 1
Overall
CADD	13.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0238% South Asian · 20/83,890 alleles

Filtering AF 0.0157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0132%

Overall 0.00136% 21/1,538,544 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0238%	4,195
Remaining individualsnot grpmax-eligible	0.00167%	59,934

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.Arg16=
Coding: c.48G>T
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:26170573 (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.Arg16Gln Uncertain significance ★★ ⚠ same residue
APP p.Arg16Trp Uncertain significance ★★ ⚠ same residue
APP p.Arg16Pro 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

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-arg16 (accessed [today's date]).

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