Is TPP2 c.784+21del pathogenic?

TPP2 c.784+21del is classified Likely benign in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-02). Very rare (popmax 0.00173%, amr); Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

How common is TPP2 c.784+21del in the general population?

TPP2 c.784+21del is very rare (popmax 0.00173%, amr) (gnomAD).

TPP2 c.784+21del

Q: What condition is associated with TPP2 c.784+21del?

TPP2 c.784+21del is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

rs763095506 · VCV1605280

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00173%, amr)

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.
Splicing
Splice region	donor +21	near-intronic (+21 nt from the splice site)
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.1	GERP -2.4, phastCons 0.016
Non-coding constraint	Z 1.08	1 kb window · o/e 0.92 · regional · uncalibrated
Overall
CADD	6.131	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00173% Admixed American · 1/57,852 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000902%

Overall 0.00143% 23/1,604,638 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00322%	31,031
Admixed Americangrpmax	0.00173%	57,852
European (non-Finnish)	0.0017%	58,818

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TPP2
Coding: c.784+21del
MANE Select: NM_001330588
dbSNP: rs763095506
Type: Deletion
Location: chr13:102623060 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98

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 p.Tyr356fs 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

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-c-784-plus-21del (accessed [today's date]).

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