Is TPP2 p.Tyr356fs (c.1066del) pathogenic?

TPP2 p.Tyr356fs (c.1066del) is classified Pathogenic in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-01). Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

TPP2 p.Tyr356fs

Q: What condition is associated with TPP2 p.Tyr356fs (c.1066del)?

TPP2 p.Tyr356fs (c.1066del) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

c.1066del · VCV4736460

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 9 of 30
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.3	GERP -0.65, phastCons 1

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

Variant & gene context

Gene: TPP2
Protein: p.Tyr356fs
Coding: c.1066del
MANE Select: NM_001330588
Type: Deletion
Location: chr13:102629529 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 356: the peptidase s8 domain

Full TPP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPP2 p.Gly1156fs Pathogenic ★ same condition
TPP2 p.Pro948fs Pathogenic ★ same condition
TPP2 c.1245-179_1245-6del Uncertain significance ★ same condition
TPP2 c.939+9_939+12del Uncertain significance ★ same condition
TPP2 c.1144+16del Benign ★ same condition
TPP2 c.1244+8del Likely benign ★ same condition
TPP2 c.1837-16del Likely benign ★ same condition
TPP2 c.1837-20_1837-17del Likely benign ★ 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/tpp2-p-tyr356fs (accessed [today's date]).

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