Is TPP2 p.Lys109Arg (c.326A>G) pathogenic?

TPP2 p.Lys109Arg (c.326A>G) is classified Uncertain significance in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-27). AlphaMissense: likely benign (0.072); Very rare (popmax 0.00133%, afr); Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

How common is TPP2 p.Lys109Arg (c.326A>G) in the general population?

TPP2 p.Lys109Arg (c.326A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TPP2 p.Lys109Arg (c.326A>G)?

AlphaMissense predicts likely benign (score 0.072) — an in-silico prediction, not a clinical call.

TPP2 p.Lys109Arg

Q: What condition is associated with TPP2 p.Lys109Arg (c.326A>G)?

TPP2 p.Lys109Arg (c.326A>G) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

c.326A>G · rs1880535184 · VCV1005297

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.072	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -11.00	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP -2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 31 kb · p 8.5e-07 · regional, not allelic
Overall
CADD	17.34	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,000 alleles

Overall 6.84e-05% 1/1,461,344 alleles · very rare

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.Lys109Arg
Coding: c.326A>G
MANE Select: NM_001330588
dbSNP: rs1880535184
Type: single nucleotide variant
Location: chr13:102614132 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 109: 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.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-p-lys109arg (accessed [today's date]).

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