Is TPP1 p.Arg339Trp (c.1015C>T) pathogenic?

TPP1 p.Arg339Trp (c.1015C>T) is classified Pathogenic/Likely pathogenic in TPP1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-03). AlphaMissense: likely pathogenic (0.7633); Very rare (popmax 0.00167%, amr); Associated with TPP1-related disorder.

What condition is associated with TPP1 p.Arg339Trp (c.1015C>T)?

TPP1 p.Arg339Trp (c.1015C>T) is associated with TPP1-related disorder, neuronal ceroid lipofuscinosis 2, autosomal recessive spinocerebellar ataxia 7 (ClinVar).

How common is TPP1 p.Arg339Trp (c.1015C>T) in the general population?

TPP1 p.Arg339Trp (c.1015C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TPP1 p.Arg339Trp (c.1015C>T)?

AlphaMissense predicts likely pathogenic (score 0.7633) — an in-silico prediction, not a clinical call.

TPP1 p.Arg339Trp

c.1015C>T · rs750428882 · VCV207586

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.7633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TPP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.7633	likely pathogenic ✓ concordant with ClinVar
REVEL	0.86	moderately pathogenic-leaning
SaProt	LLR -12.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -2.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,851 bp · p 0.14 · regional, not allelic
Overall
CADD	26.8	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 0.00167% Admixed American · 1/60,020 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,613,896 alleles · very rare exomes 9/1,461,600 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
South Asian	0.0011%	91,068
European (non-Finnish)	0.000593%	168,575

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.Arg339Trp
Coding: c.1015C>T
MANE Select: NM_000391
dbSNP: rs750428882
Type: single nucleotide variant
Location: chr11:6616375 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 339: an α-helix; the peptidase s53 domain; a UniProt-annotated variant site (in cln2)

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

Disease context

TPP1-related disorder

Also linked: neuronal ceroid lipofuscinosis 2 autosomal recessive spinocerebellar ataxia 7 neuronal ceroid lipofuscinosis

Similar variants

TPP1 p.Arg339Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
TPP1 p.Arg339Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TPP1 p.Arg339= Likely benign ★ same residue
TPP1 c.1075+2T>C Pathogenic/Likely pathogenic ★★ same condition
TPP1 c.1076-2A>G Pathogenic/Likely pathogenic ★★ same condition
TPP1 c.1076-2A>T Pathogenic ★★ same condition
TPP1 c.1146-1G>A Likely pathogenic ★★ same condition
TPP1 c.1425+1G>A Likely pathogenic ★★ 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/tpp1-p-arg339trp (accessed [today's date]).

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