Is TPP2 p.Val504Asp (c.1511T>A) pathogenic?

TPP2 p.Val504Asp (c.1511T>A) is classified Uncertain significance in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-03). AlphaMissense: likely pathogenic (0.9962); Absent from gnomAD v4.1; Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

How common is TPP2 p.Val504Asp (c.1511T>A) in the general population?

TPP2 p.Val504Asp (c.1511T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPP2 p.Val504Asp (c.1511T>A)?

AlphaMissense predicts likely pathogenic (score 0.9962) — an in-silico prediction, not a clinical call.

TPP2 p.Val504Asp

Q: What condition is associated with TPP2 p.Val504Asp (c.1511T>A)?

TPP2 p.Val504Asp (c.1511T>A) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

c.1511T>A · rs2503984168 · VCV2013731

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9962 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9962	likely pathogenic · top 6% in TPP2
REVEL	0.797	moderately pathogenic-leaning
SaProt	LLR -13.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 13 kb · p 1.2e-10 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TPP2
Protein: p.Val504Asp
Coding: c.1511T>A
MANE Select: NM_001330588
dbSNP: rs2503984168
Type: single nucleotide variant
Location: chr13:102636225 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 504: 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-val504asp (accessed [today's date]).

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