TPP2 p.Ala1198=

Q: Is TPP2 p.Ala1198= (c.3594A>G) pathogenic?

TPP2 p.Ala1198= (c.3594A>G) is classified Benign in TPP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). Common (popmax 17.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

Q: What condition is associated with TPP2 p.Ala1198= (c.3594A>G)?

TPP2 p.Ala1198= (c.3594A>G) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

Q: How common is TPP2 p.Ala1198= (c.3594A>G) in the general population?

TPP2 p.Ala1198= (c.3594A>G) is common (popmax 17.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3594A>G · rs2230856 · VCV1164962

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 17.6%, afr) — too common for a highly-penetrant pathogenic allele

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
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.38	GERP -1.2, phastCons 0.64
Overall
CADD	7.416	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 17.6% African / African-American · 13,099/74,362 alleles

Filtering AF 17.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.3%

Overall 5.64% 90,278/1,600,500 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	17.6%	6
Middle Eastern	14.5%	7
East Asian	12.2%	8
South Asian	8.19%	12
Ashkenazi Jewishnot grpmax-eligible	8.14%	12
Remaining individualsnot grpmax-eligible	7.21%	14
Amishnot grpmax-eligible	6.58%	15
Admixed American	4.79%	21
European (non-Finnish)	4.42%	23
Finnishnot grpmax-eligible	3.26%	31

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
Protein: p.Ala1198=
Coding: c.3594A>G
MANE Select: NM_001330588
dbSNP: rs2230856
Type: single nucleotide variant
Location: chr13:102676310 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 1198: a UniProt-annotated variant site (in imd78; loss of expression)

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.Ala1198Val Uncertain significance ★ ⚠ same residue
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

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-ala1198 (accessed [today's date]).

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