Is APP p.Tyr538= (c.1614T>C) pathogenic?

APP p.Tyr538= (c.1614T>C) is classified Benign in APP (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-19). Common (popmax 8.08%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Alzheimer disease.

What condition is associated with APP p.Tyr538= (c.1614T>C)?

APP p.Tyr538= (c.1614T>C) is associated with Alzheimer disease (ClinVar).

APP p.Tyr538=

Q: How common is APP p.Tyr538= (c.1614T>C) in the general population?

APP p.Tyr538= (c.1614T>C) is common (popmax 8.08%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1614T>C · rs45537238 · VCV339636

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 8.08%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Alzheimer disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5.7	GERP -5.4
Overall
CADD	0.204	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.08% African / African-American · 6,062/75,016 alleles

Filtering AF 7.91% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.84%

Overall 0.438% 7,063/1,614,066 alleles · common exomes 3,573/1,461,752 · genomes 3,490/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.08%	12
Admixed American	0.667%	150
Middle Eastern	0.594%	168
Remaining individualsnot grpmax-eligible	0.504%	198
Ashkenazi Jewishnot grpmax-eligible	0.176%	569
European (non-Finnish)	0.0155%	6,448
South Asian	0.0154%	6,503
East Asian	0.00223%	44,888

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.Tyr538=
Coding: c.1614T>C
MANE Select: NM_000484
dbSNP: rs45537238
Type: single nucleotide variant
Location: chr21:25954663 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 538: the e2 domain; an α-helix; the 'collagen-binding' region

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.Tyr538His Uncertain significance ★ ⚠ same residue
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

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-tyr538 (accessed [today's date]).

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