Is TPP2 p.Lys1112Arg (c.3335A>G) pathogenic?

TPP2 p.Lys1112Arg (c.3335A>G) is classified Conflicting classifications of pathogenicity in TPP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1525); Rare (popmax 0.212%, afr); Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

How common is TPP2 p.Lys1112Arg (c.3335A>G) in the general population?

TPP2 p.Lys1112Arg (c.3335A>G) is rare (popmax 0.212%, afr) (gnomAD).

What do computational predictors say about TPP2 p.Lys1112Arg (c.3335A>G)?

AlphaMissense predicts likely benign (score 0.1525) — an in-silico prediction, not a clinical call.

TPP2 p.Lys1112Arg

Q: What condition is associated with TPP2 p.Lys1112Arg (c.3335A>G)?

TPP2 p.Lys1112Arg (c.3335A>G) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

c.3335A>G · rs141032667 · VCV709114

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1525 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.212%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.1525	likely benign
REVEL	0.253	benign-leaning
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 11 kb · p 0.9 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K1099R vs ClinVar K1112R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.212% African / African-American · 159/75,048 alleles

Filtering AF 0.185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.175%

Overall 0.0127% 205/1,613,832 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.212%	472
Admixed American	0.0367%	2,728
Remaining individualsnot grpmax-eligible	0.0256%	3,906
Middle Eastern	0.0165%	6,056
European (non-Finnish)	0.000593%	168,551

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.Lys1112Arg
Coding: c.3335A>G
MANE Select: NM_001330588
dbSNP: rs141032667
Type: single nucleotide variant
Location: chr13:102664889 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 1112: 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.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-lys1112arg (accessed [today's date]).

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