Is TPP2 p.Arg889Ter (c.2665C>T) pathogenic?

TPP2 p.Arg889Ter (c.2665C>T) is classified Likely pathogenic in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-17). Very rare (popmax 8.48e-05%, nfe).

How common is TPP2 p.Arg889Ter (c.2665C>T) in the general population?

TPP2 p.Arg889Ter (c.2665C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

TPP2 p.Arg889Ter

c.2665C>T · rs1419487180 · VCV1804520

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 22 of 30
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,902 alleles

Overall 6.86e-05% 1/1,457,398 alleles · very rare

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.Arg889Ter
Coding: c.2665C>T
MANE Select: NM_001330588
dbSNP: rs1419487180
Type: single nucleotide variant
Location: chr13:102648943 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 889: a UniProt-annotated variant site (in imd78; loss of expression)

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

Similar variants

TPP2 p.Arg889Gln Uncertain significance ★ ⚠ same residue
TPP2 p.Ala1143Ser Uncertain significance ★★ ⚠ same type
TPP2 p.Ala460Thr Uncertain significance ★★ ⚠ same type
TPP2 p.Ala619Thr Uncertain significance ★★ ⚠ same type
TPP2 p.Ala648Asp Uncertain significance ★★ ⚠ same type
TPP2 p.Arg1072Gln Uncertain significance ★★ ⚠ same type
TPP2 p.Arg598His Uncertain significance ★★ ⚠ same type
TPP2 p.Arg893Cys Uncertain significance ★★ ⚠ same type

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-arg889ter (accessed [today's date]).

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