Is TPR p.Arg2145Pro (c.6434G>C) pathogenic?

TPR p.Arg2145Pro (c.6434G>C) is classified Uncertain significance in TPR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely pathogenic (0.9913); Very rare (popmax 8.48e-05%, nfe).

How common is TPR p.Arg2145Pro (c.6434G>C) in the general population?

TPR p.Arg2145Pro (c.6434G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TPR p.Arg2145Pro (c.6434G>C)?

AlphaMissense predicts likely pathogenic (score 0.9913) — an in-silico prediction, not a clinical call.

TPR p.Arg2145Pro

c.6434G>C · rs1466614054 · VCV2251464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9913 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9913	likely pathogenic · top 2% in TPR
REVEL	0.694	pathogenic-leaning
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.66, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 4,038 bp · p 3.1e-11 · regional, not allelic
Overall
CADD	26.9	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 8.48e-05% European (non-Finnish) · 1/1,179,708 alleles

Overall 6.85e-05% 1/1,460,680 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: TPR
Protein: p.Arg2145Pro
Coding: c.6434G>C
MANE Select: NM_003292
dbSNP: rs1466614054
Type: single nucleotide variant
Location: chr1:186322345 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.60 · 4 PDB

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

Similar variants

TPR p.Thr1751Ala Uncertain significance ★★ ⚠ same type
TPR p.Arg1832His Likely benign ★★ same type
TPR p.Arg467= Benign/Likely benign ★★ same type
TPR p.Leu1314= Benign ★★ same type
TPR p.Pro2168Ser Benign ★★ same type
TPR p.Thr762= Benign ★★ same type
TPR c.2610+5G>A Uncertain significance ★ same type
TPR p.Ala1025Thr 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/tpr-p-arg2145pro (accessed [today's date]).

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