Is TPP2 p.Trp437Arg (c.1309T>C) pathogenic?

TPP2 p.Trp437Arg (c.1309T>C) is classified Uncertain significance in TPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-05). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1.

How common is TPP2 p.Trp437Arg (c.1309T>C) in the general population?

TPP2 p.Trp437Arg (c.1309T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPP2 p.Trp437Arg (c.1309T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

TPP2 p.Trp437Arg

c.1309T>C · rs2503974226 · VCV1801977

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 1% in TPP2
REVEL	0.582	indeterminate
SaProt	LLR -15.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.89 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 6,202 bp · p 1.5e-15 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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.Trp437Arg
Coding: c.1309T>C
MANE Select: NM_001330588
dbSNP: rs2503974226
Type: single nucleotide variant
Location: chr13:102634014 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.98
Residue 437: the peptidase s8 domain

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

Similar variants

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
TPP2 p.Arg902His 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-trp437arg (accessed [today's date]).

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