Is APP p.Cys117= (c.351C>T) pathogenic?

APP p.Cys117= (c.351C>T) is classified Likely benign in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). Very rare (popmax 0.00267%, afr); Associated with Alzheimer disease.

What condition is associated with APP p.Cys117= (c.351C>T)?

APP p.Cys117= (c.351C>T) is associated with Alzheimer disease (ClinVar).

How common is APP p.Cys117= (c.351C>T) in the general population?

APP p.Cys117= (c.351C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

APP p.Cys117=

c.351C>T · VCV3626302

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Alzheimer disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.08	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.5	GERP 1.7, phastCons 1
Overall
CADD	13.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,916 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00204% 33/1,613,978 alleles · very rare exomes 29/1,461,812 · genomes 4/152,166 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,458
European (non-Finnish)	0.00263%	38,064

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.Cys117=
Coding: c.351C>T
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:26089947 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 117: the e1 domain; a β-strand; the 'gfld subdomain' region; a disulfide bond

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-cys117 (accessed [today's date]).

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