Is TPP2 p.Ala41Thr (c.121G>A) pathogenic?

TPP2 p.Ala41Thr (c.121G>A) is classified Conflicting classifications of pathogenicity in TPP2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.819); Rare (popmax 0.235%, nfe); Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

How common is TPP2 p.Ala41Thr (c.121G>A) in the general population?

TPP2 p.Ala41Thr (c.121G>A) is rare (popmax 0.235%, nfe) (gnomAD).

What do computational predictors say about TPP2 p.Ala41Thr (c.121G>A)?

AlphaMissense predicts likely pathogenic (score 0.819) — an in-silico prediction, not a clinical call.

TPP2 p.Ala41Thr

Q: What condition is associated with TPP2 p.Ala41Thr (c.121G>A)?

TPP2 p.Ala41Thr (c.121G>A) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

c.121G>A · rs200366836 · VCV791081

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.819 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.235%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.819	likely pathogenic
REVEL	0.471	indeterminate
SaProt	LLR -15.51	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 31 kb · p 8.5e-07 · regional, not allelic
Overall
CADD	28.2	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 0.235% European (non-Finnish) · 2,764/1,175,918 alleles

Filtering AF 0.228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.225%

Overall 0.217% 3,475/1,603,500 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.826%	121
European (non-Finnish)grpmax	0.235%	425
Remaining individualsnot grpmax-eligible	0.207%	484
Admixed American	0.0774%	1,292
African / African-American	0.0216%	4,633
South Asian	0.00111%	90,158

Finnish 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.Ala41Thr
Coding: c.121G>A
MANE Select: NM_001330588
dbSNP: rs200366836
Type: single nucleotide variant
Location: chr13:102597159 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 41: 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-ala41thr (accessed [today's date]).

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