Is TPP2 p.Pro31Leu (c.92C>T) pathogenic?

TPP2 p.Pro31Leu (c.92C>T) is classified Uncertain significance in TPP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-06). AlphaMissense: ambiguous (0.3492); Rare (popmax 0.167%, amr); Associated with Inborn genetic diseases.

What condition is associated with TPP2 p.Pro31Leu (c.92C>T)?

TPP2 p.Pro31Leu (c.92C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TPP2 p.Pro31Leu (c.92C>T) in the general population?

TPP2 p.Pro31Leu (c.92C>T) is rare (popmax 0.167%, amr) (gnomAD).

What do computational predictors say about TPP2 p.Pro31Leu (c.92C>T)?

AlphaMissense predicts ambiguous (score 0.3492) — an in-silico prediction, not a clinical call.

TPP2 p.Pro31Leu

c.92C>T · rs375925353 · VCV478057

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3492 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.167%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3492	ambiguous
REVEL	0.514	indeterminate
SaProt	LLR -15.43	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 2.4, phastCons 0.99
Regional constraint	o/e 0.75	unconstrained · MANE · 31 kb · p 8.5e-07 · regional, not allelic
Overall
CADD	31.0	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 0.167% Admixed American · 100/59,924 alleles

Filtering AF 0.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.13%

Overall 0.0165% 265/1,610,440 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.167%	599
Remaining individualsnot grpmax-eligible	0.0466%	2,147
European (non-Finnish)	0.0107%	9,357
African / African-American	0.00937%	10,674
South Asian	0.0022%	45,373
Finnishnot grpmax-eligible	0.00157%	63,602

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.Pro31Leu
Coding: c.92C>T
MANE Select: NM_001330588
dbSNP: rs375925353
Type: single nucleotide variant
Location: chr13:102597130 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 31: the peptidase s8 domain

Full TPP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPP2 p.Pro31Ala Uncertain significance ★★ ⚠ same residue
TPP2 p.Pro31Ser Uncertain significance ★ ⚠ same residue
TPP2 p.Ala1143Ser Uncertain significance ★★ ⚠ same condition
TPP2 p.Ala460Thr Uncertain significance ★★ ⚠ same condition
TPP2 p.Arg598His Uncertain significance ★★ ⚠ same condition
TPP2 p.Arg902His Uncertain significance ★★ ⚠ same condition
TPP2 p.Asn771Ser Uncertain significance ★★ ⚠ same condition
TPP2 p.Cys710Tyr 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-pro31leu (accessed [today's date]).

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