Is TPP2 p.Val512Ile (c.1534G>A) pathogenic?

TPP2 p.Val512Ile (c.1534G>A) is classified Benign/Likely benign in TPP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.0581); Low-frequency (popmax 1.12%, afr); Associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

How common is TPP2 p.Val512Ile (c.1534G>A) in the general population?

TPP2 p.Val512Ile (c.1534G>A) is low-frequency (popmax 1.12%, afr) (gnomAD).

What do computational predictors say about TPP2 p.Val512Ile (c.1534G>A)?

AlphaMissense predicts likely benign (score 0.0581) — an in-silico prediction, not a clinical call.

TPP2 p.Val512Ile

Q: What condition is associated with TPP2 p.Val512Ile (c.1534G>A)?

TPP2 p.Val512Ile (c.1534G>A) is associated with Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (ClinVar).

c.1534G>A · rs73578896 · VCV544313

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0581 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.12%, afr)

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	0.0581	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.068	GERP -2.8, phastCons 0.087
Regional constraint	o/e 0.70	unconstrained · MANE · 13 kb · p 1.2e-10 · regional, not allelic
Overall
CADD	14.22	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 1.12% African / African-American · 840/74,866 alleles

Filtering AF 1.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.03%

Overall 0.0577% 931/1,612,336 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.12%	89
Remaining individualsnot grpmax-eligible	0.0625%	1,601
Admixed American	0.0436%	2,296
Middle Eastern	0.0165%	6,054
Finnishnot grpmax-eligible	0.00782%	12,780
South Asian	0.0022%	45,402
European (non-Finnish)	0.00153%	65,520

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.Val512Ile
Coding: c.1534G>A
MANE Select: NM_001330588
dbSNP: rs73578896
Type: single nucleotide variant
Location: chr13:102636248 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98

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-val512ile (accessed [today's date]).

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