Is TPP2 p.Ile424Val (c.1270A>G) pathogenic?

TPP2 p.Ile424Val (c.1270A>G) is classified Uncertain significance in TPP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-29). AlphaMissense: likely benign (0.0821); Ultra-rare (popmax 0.0493%, mid); Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

How common is TPP2 p.Ile424Val (c.1270A>G) in the general population?

TPP2 p.Ile424Val (c.1270A>G) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about TPP2 p.Ile424Val (c.1270A>G)?

AlphaMissense predicts likely benign (score 0.0821) — an in-silico prediction, not a clinical call.

TPP2 p.Ile424Val

Q: What condition is associated with TPP2 p.Ile424Val (c.1270A>G)?

TPP2 p.Ile424Val (c.1270A>G) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency, immunodeficiency 78 with autoimmunity and developmental delay (ClinVar).

c.1270A>G · rs146267750 · VCV949468

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0821 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

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	0.0821	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -5.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 6,202 bp · p 1.5e-15 · regional, not allelic
Overall
CADD	18.06	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0493% Middle Eastern · 3/6,082 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00607% 98/1,613,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,960
South Asian	0.00878%	11,386
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00568%	17,612
Admixed American	0.005%	19,998
African / African-American	0.004%	24,975

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.Ile424Val
Coding: c.1270A>G
MANE Select: NM_001330588
dbSNP: rs146267750
Type: single nucleotide variant
Location: chr13:102633975 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 424: 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

Also linked: immunodeficiency 78 with autoimmunity and developmental delay

Similar variants

TPP2 p.Ile424Met 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-ile424val (accessed [today's date]).

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