Is TPP2 p.Ile248Val (c.742A>G) pathogenic?

TPP2 p.Ile248Val (c.742A>G) is classified Uncertain significance in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-05). AlphaMissense: likely benign (0.0829); 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.Ile248Val (c.742A>G) in the general population?

TPP2 p.Ile248Val (c.742A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TPP2 p.Ile248Val (c.742A>G)?

AlphaMissense predicts likely benign (score 0.0829) — an in-silico prediction, not a clinical call.

TPP2 p.Ile248Val

Q: What condition is associated with TPP2 p.Ile248Val (c.742A>G)?

TPP2 p.Ile248Val (c.742A>G) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

c.742A>G · rs771533347 · VCV1354229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0829 · 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	0.0829	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -10.03	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 9.3	GERP 2.2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 31 kb · p 8.5e-07 · regional, not allelic
Overall
CADD	20.5	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 · 1/74,918 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,613,716 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,464
African / African-Americangrpmax	0.00133%	74,918
European (non-Finnish)	0.000508%	196,660

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

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.Ile248Val
Coding: c.742A>G
MANE Select: NM_001330588
dbSNP: rs771533347
Type: single nucleotide variant
Location: chr13:102622998 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 248: 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-ile248val (accessed [today's date]).

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