Is TPP2 p.Ile68Thr (c.203T>C) pathogenic?

TPP2 p.Ile68Thr (c.203T>C) is classified Uncertain significance in TPP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-07). AlphaMissense: ambiguous (0.4249); Ultra-rare (popmax 0.012%, afr); Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

How common is TPP2 p.Ile68Thr (c.203T>C) in the general population?

TPP2 p.Ile68Thr (c.203T>C) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about TPP2 p.Ile68Thr (c.203T>C)?

AlphaMissense predicts ambiguous (score 0.4249) — an in-silico prediction, not a clinical call.

TPP2 p.Ile68Thr

Q: What condition is associated with TPP2 p.Ile68Thr (c.203T>C)?

TPP2 p.Ile68Thr (c.203T>C) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

c.203T>C · rs796459178 · VCV1910916

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4249 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.4249	ambiguous
REVEL	0.523	indeterminate
SaProt	LLR -11.18	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 31 kb · p 8.5e-07 · regional, not allelic
Overall
CADD	26.3	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 0.012% African / African-American · 9/74,992 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000744% 12/1,613,444 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,332
Admixed American	0.00167%	59,834
Remaining individualsnot grpmax-eligible	0.0016%	62,474
South Asian	0.0011%	90,828

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.Ile68Thr
Coding: c.203T>C
MANE Select: NM_001330588
dbSNP: rs796459178
Type: single nucleotide variant
Location: chr13:102604830 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 68: 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.Ile68Val 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-ile68thr (accessed [today's date]).

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