# NM_001330588.2(TPP2):c.1479A>G (p.Glu493=)

https://sugi.bio/variant/tpp2-p-glu493

## Summary

**TPP2 p.Glu493= (c.1479A>G)** is classified **Uncertain significance** in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-15). Very rare (popmax 0.000254%, nfe); Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs760707396 · 1 submitter · 1 linked condition · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the TPP2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TPP2](https://sugi.bio/atlas/gene/TPP2/) |
| Protein change (HGVS p.) | p.Glu493= |
| Coding change (HGVS c.) | c.1479A>G |
| MANE Select transcript | [NM_001330588](https://www.ncbi.nlm.nih.gov/nuccore/NM_001330588) |
| dbSNP | [rs760707396](https://www.ncbi.nlm.nih.gov/snp/rs760707396/) |
| Variant type | single nucleotide variant |
| Location | chr13:102635672-102635672 (GRCh38) |
| ClinVar | [VCV1902210](https://www.ncbi.nlm.nih.gov/clinvar/variation/1902210/) |

**All HGVS expressions:** `LRG_1341:g.43687A>G`, `LRG_1341t1:c.1479A>G`, `NC_000013.10:g.103288022A>G`, `NC_000013.11:g.102635672A>G`, `NG_063544.1:g.43687A>G`, `NM_001330588.2:c.1479A>G`, `NM_001367947.1:c.1479A>G`, `NM_003291.4:c.1479A>G`, `NR_160411.1:n.1532A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.73) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.008, GERP 1.38, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 20.7**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.05**, acceptor gain **0.00**, donor gain **0.73**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.05**, acceptor gain **0.00**, donor gain **0.73**.
- Pangolin: Δ**0.48** (gain), gain 0.48 / loss 0.20. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,730 in the highest group · 37/1,613,170 alleles overall — very rare (popmax 0.000254%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0503% | 1,987 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,231 |
| European (non-Finnish) (grpmax) | 0.000254% | 393,244 |

Finnish shows a higher raw frequency than the grpmax group. 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.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TPP2** population constraint: LOEUF 0.29, pLI 1, missense-Z 4.5833. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **immunodeficiency 78 with autoimmunity and developmental delay** — Definitive (AR)

## Protein context {#protein}

Residue **493** lies in the peptidase s8 domain.

AlphaFold model confidence (whole protein): pLDDT 91.98, 80% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of TPP2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TPP2's established molecular role includes aminopeptidase activity. p.Glu493= falls in the peptidase s8 domain.


### Pathways affected {#pathways}

TPP2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** aminopeptidase activity, identical protein binding.

**Biological process:** intracellular amino acid homeostasis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-15 |

## Associated conditions {#conditions}

[Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency](https://sugi.bio/atlas/disease/evans-syndrome-immunodeficiency-and-premature-immunosenescence-associated-with-tripeptidyl-peptidase-ii-deficiency/).

**Reported phenotype names (ClinVar):** Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

## Similar variants {#similar}

Related TPP2 variant pages (same residue, condition, or type): [TPP2 p.Ala619Thr](/variant/tpp2-p-ala619thr), [TPP2 p.Ala648Asp](/variant/tpp2-p-ala648asp), [TPP2 p.Arg1072Gln](/variant/tpp2-p-arg1072gln), [TPP2 p.Arg893Cys](/variant/tpp2-p-arg893cys), [TPP2 p.Asn1192Ser](/variant/tpp2-p-asn1192ser), [TPP2 p.Asn1227Ser](/variant/tpp2-p-asn1227ser), [TPP2 p.Asp86His](/variant/tpp2-p-asp86his), [TPP2 p.Cys1231Tyr](/variant/tpp2-p-cys1231tyr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1902210). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*