Is TPP1 p.Pro499Arg (c.1496C>G) pathogenic?

TPP1 p.Pro499Arg (c.1496C>G) is classified Uncertain significance in TPP1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-25). AlphaMissense: likely benign (0.2059); Ultra-rare (popmax 0.0117%, amr); Associated with neuronal ceroid lipofuscinosis 2.

What condition is associated with TPP1 p.Pro499Arg (c.1496C>G)?

TPP1 p.Pro499Arg (c.1496C>G) is associated with neuronal ceroid lipofuscinosis 2 (ClinVar).

How common is TPP1 p.Pro499Arg (c.1496C>G) in the general population?

TPP1 p.Pro499Arg (c.1496C>G) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

How is CLN2 disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TPP1 p.Pro499Arg (c.1496C>G)?

AlphaMissense predicts likely benign (score 0.2059) — an in-silico prediction, not a clinical call.

TPP1 p.Pro499Arg

c.1496C>G · rs773707856 · VCV457943

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2059 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neuronal ceroid lipofuscinosis 2

Computational evidence

Protein change
AlphaMissense	0.2059	likely benign
REVEL	0.575	indeterminate
SaProt	LLR -12.10	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.099, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,851 bp · p 0.14 · regional, not allelic
Overall
CADD	24.8	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 0.0117% Admixed American · 7/59,998 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.0044% 71/1,614,024 alleles · ultra-rare exomes 64/1,461,870 · genomes 7/152,154 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,571
European (non-Finnish)	0.005%	20,001
Remaining individualsnot grpmax-eligible	0.0048%	20,828
East Asian	0.00223%	44,884
African / African-American	0.00133%	74,912

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.Pro499Arg
Coding: c.1496C>G
MANE Select: NM_000391
dbSNP: rs773707856
Type: single nucleotide variant
Location: chr11:6614921 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 499: an α-helix; the peptidase s53 domain

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

Disease context

neuronal ceroid lipofuscinosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CLN2 disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

TPP1 p.Pro499Ala Uncertain significance ★★ ⚠ same residue
TPP1 p.Pro499Thr Uncertain significance ★★ ⚠ same residue
TPP1 p.Pro499Leu Uncertain significance ★ ⚠ same residue
TPP1 p.Pro499= Benign/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

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-pro499arg (accessed [today's date]).

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