Is TPP2 p.Pro713Thr (c.2137C>A) pathogenic?

TPP2 p.Pro713Thr (c.2137C>A) is classified Uncertain significance in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-18). AlphaMissense: likely benign (0.1199); Absent from gnomAD v4.1; Associated with immunodeficiency 78 with autoimmunity and developmental delay.

What condition is associated with TPP2 p.Pro713Thr (c.2137C>A)?

TPP2 p.Pro713Thr (c.2137C>A) is associated with immunodeficiency 78 with autoimmunity and developmental delay (ClinVar).

How common is TPP2 p.Pro713Thr (c.2137C>A) in the general population?

TPP2 p.Pro713Thr (c.2137C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPP2 p.Pro713Thr (c.2137C>A)?

AlphaMissense predicts likely benign (score 0.1199) — an in-silico prediction, not a clinical call.

TPP2 p.Pro713Thr

c.2137C>A · rs2504012862 · VCV2437220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1199 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 78 with autoimmunity and developmental delay

Computational evidence

Protein change
AlphaMissense	0.1199	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -7.58	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 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 13 kb · p 1.2e-10 · regional, not allelic
Overall
CADD	22.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TPP2
Protein: p.Pro713Thr
Coding: c.2137C>A
MANE Select: NM_001330588
dbSNP: rs2504012862
Type: single nucleotide variant
Location: chr13:102643338 (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

immunodeficiency 78 with autoimmunity and developmental delay — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPP2 p.Pro713= Likely benign ★ same residue
TPP2 p.Gln1154Pro Uncertain significance ★★ ⚠ same condition
TPP2 p.Glu1025Gly Uncertain significance ★★ ⚠ same condition
TPP2 p.Ile424Val Uncertain significance ★★ ⚠ same condition
TPP2 p.Ile746Asn Uncertain significance ★★ ⚠ same condition
TPP2 p.Ser801Asn Uncertain significance ★★ ⚠ same condition
TPP2 p.Thr676Ile Uncertain significance ★★ ⚠ same condition
TPP2 c.1016+17A>G Likely benign ★★ 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-pro713thr (accessed [today's date]).

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