Is TPP2 c.620+3A>G pathogenic?

TPP2 c.620+3A>G is classified Uncertain significance in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-12). Ultra-rare (popmax 0.0283%, afr); Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

How common is TPP2 c.620+3A>G in the general population?

TPP2 c.620+3A>G is ultra-rare (popmax 0.0283%, afr) (gnomAD).

TPP2 c.620+3A>G

Q: What condition is associated with TPP2 c.620+3A>G?

TPP2 c.620+3A>G is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

rs374850648 · VCV2069780

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, afr)

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/SpliceAI carries the signal.
Splicing
Splice region	donor +3	donor splice region (+3, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.72	donor loss · deltas
Pangolin	Δ0.31	loss · gain 0.15 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.1	GERP 0.027, phastCons 1
Non-coding constraint	Z 2.10	1 kb window · o/e 0.84 · regional · uncalibrated
Overall
CADD	10.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0283% African / African-American · 21/74,234 alleles

Filtering AF 0.0189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0159%

Overall 0.00137% 22/1,601,342 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0283%	3,535
Admixed American	0.00176%	56,818

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.620+3A>G
MANE Select: NM_001330588
dbSNP: rs374850648
Type: single nucleotide variant
Location: chr13:102618849 (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.Ala619Thr Uncertain significance ★★ ⚠ same condition
TPP2 p.Ala648Asp Uncertain significance ★★ ⚠ same condition
TPP2 p.Arg1072Gln Uncertain significance ★★ ⚠ same condition
TPP2 p.Arg893Cys Uncertain significance ★★ ⚠ same condition
TPP2 p.Asn1192Ser Uncertain significance ★★ ⚠ same condition
TPP2 p.Asn1227Ser Uncertain significance ★★ ⚠ same condition
TPP2 p.Asp86His Uncertain significance ★★ ⚠ same condition
TPP2 p.Cys1231Tyr Uncertain significance ★★ ⚠ 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-620-plus-3a-g (accessed [today's date]).

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