Is TPP2 p.Ser801Asn (c.2402G>A) pathogenic?

TPP2 p.Ser801Asn (c.2402G>A) is classified Uncertain significance in TPP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.0952); Ultra-rare (popmax 0.0277%, nfe); Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

How common is TPP2 p.Ser801Asn (c.2402G>A) in the general population?

TPP2 p.Ser801Asn (c.2402G>A) is ultra-rare (popmax 0.0277%, nfe) (gnomAD).

What do computational predictors say about TPP2 p.Ser801Asn (c.2402G>A)?

AlphaMissense predicts likely benign (score 0.0952) — an in-silico prediction, not a clinical call.

TPP2 p.Ser801Asn

Q: What condition is associated with TPP2 p.Ser801Asn (c.2402G>A)?

TPP2 p.Ser801Asn (c.2402G>A) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency, immunodeficiency 78 with autoimmunity and developmental delay (ClinVar).

c.2402G>A · rs140329690 · VCV857859

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0952 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0277%, nfe)

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	0.0952	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 2.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 13 kb · p 1.2e-10 · regional, not allelic
Overall
CADD	19.06	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 0.0277% European (non-Finnish) · 327/1,179,238 alleles

Filtering AF 0.0252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0242%

Overall 0.0214% 345/1,612,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0277%	3,606
Middle Eastern	0.0165%	6,046
Remaining individualsnot grpmax-eligible	0.016%	6,238
African / African-American	0.00535%	18,696
Finnishnot grpmax-eligible	0.00313%	31,965
Admixed American	0.00167%	59,758

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.Ser801Asn
Coding: c.2402G>A
MANE Select: NM_001330588
dbSNP: rs140329690
Type: single nucleotide variant
Location: chr13:102646302 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 801: a UniProt-annotated variant site (in imd78; loss of expression)

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.Ser801= Likely benign ★ same residue
TPP2 p.Ser801Arg 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

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-ser801asn (accessed [today's date]).

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