Is APP p.Tyr757= (c.2271C>T) pathogenic?

APP p.Tyr757= (c.2271C>T) is classified Likely benign in APP (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-18). Very rare (popmax 0.00891%, eas); Associated with Alzheimer disease.

What condition is associated with APP p.Tyr757= (c.2271C>T)?

APP p.Tyr757= (c.2271C>T) is associated with Alzheimer disease (ClinVar).

How common is APP p.Tyr757= (c.2271C>T) in the general population?

APP p.Tyr757= (c.2271C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

APP p.Tyr757=

c.2271C>T · rs774518756 · VCV1936980

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Conditions

Alzheimer disease

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 -4.9	GERP -3.9
Overall
CADD	0.379	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,896 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00198% 32/1,613,842 alleles · very rare exomes 28/1,461,708 · genomes 4/152,134 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,224
African / African-American	0.00267%	37,450
European (non-Finnish)	0.0022%	45,385

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.Tyr757=
Coding: c.2271C>T
MANE Select: NM_000484
dbSNP: rs774518756
Type: single nucleotide variant
Location: chr21:25881712 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 757: a β-strand; the 'required for the interaction with kif5b and for anterograde transport in axons' region; a modified residue (phosphotyrosine)

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-tyr757 (accessed [today's date]).

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