Is TPP1 p.Arg206Pro (c.617G>C) pathogenic?

TPP1 p.Arg206Pro (c.617G>C) is classified Likely pathogenic in TPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-30). AlphaMissense: likely pathogenic (0.9913); Very rare (popmax 0.00223%, eas).

How common is TPP1 p.Arg206Pro (c.617G>C) in the general population?

TPP1 p.Arg206Pro (c.617G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about TPP1 p.Arg206Pro (c.617G>C)?

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

TPP1 p.Arg206Pro

c.617G>C · rs121908209 · VCV1068193

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9913	likely pathogenic ✓ concordant with ClinVar · top 1% in TPP1
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -15.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,851 bp · p 0.14 · regional, not allelic
Overall
CADD	29.4	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 0.00223% East Asian · 1/44,884 alleles

Overall 6.2e-05% 1/1,614,124 alleles · very rare exomes 1/1,461,860 · genomes 0/152,264 · joint denominator

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: TPP1
Protein: p.Arg206Pro
Coding: c.617G>C
MANE Select: NM_000391
dbSNP: rs121908209
Type: single nucleotide variant
Location: chr11:6617045 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 206: the peptidase s53 domain; a UniProt-annotated variant site (in cln2; displays no residual enzyme activity; altered intracellular trafficking); a UniProt-annotated variant site (in cln2); an α-helix

Full TPP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TPP1 p.Arg206Cys Pathogenic ★★ same residue
TPP1 p.Arg206His Pathogenic/Likely pathogenic ★★ ⚠ same residue
TPP1 p.Arg206Leu Likely pathogenic ★ same residue
TPP1 p.Arg206fs Pathogenic ★ same residue
TPP1 c.1075+2T>C Pathogenic/Likely pathogenic ★★ same type
TPP1 c.1076-2A>G Pathogenic/Likely pathogenic ★★ same type
TPP1 c.1076-2A>T Pathogenic ★★ same type
TPP1 c.1146-1G>A Likely pathogenic ★★ 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/tpp1-p-arg206pro (accessed [today's date]).

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