Is PPT1 p.Pro189Arg (c.566C>G) pathogenic?

PPT1 p.Pro189Arg (c.566C>G) is classified Likely pathogenic in PPT1 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9133); Very rare (popmax 0.00223%, eas); Associated with neuronal ceroid lipofuscinosis 1.

What condition is associated with PPT1 p.Pro189Arg (c.566C>G)?

PPT1 p.Pro189Arg (c.566C>G) is associated with neuronal ceroid lipofuscinosis 1 (ClinVar).

How common is PPT1 p.Pro189Arg (c.566C>G) in the general population?

PPT1 p.Pro189Arg (c.566C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

How is CLN1 disease inherited?

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

What do computational predictors say about PPT1 p.Pro189Arg (c.566C>G)?

AlphaMissense predicts likely pathogenic (score 0.9133) — an in-silico prediction, not a clinical call.

PPT1 p.Pro189Arg

c.566C>G · rs386833658 · VCV56207

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 1

Computational evidence

Protein change
AlphaMissense	0.9133	likely pathogenic ✓ concordant with ClinVar
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -15.14	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 23 kb · p 0.052 · regional, not allelic
Overall
CADD	31.0	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 · 1/44,882 alleles

Overall 6.2e-05% 1/1,613,904 alleles · very rare exomes 0/1,461,818 · genomes 1/152,086 · 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: PPT1
Protein: p.Pro189Arg
Coding: c.566C>G
MANE Select: NM_000310
dbSNP: rs386833658
Type: single nucleotide variant
Location: chr1:40080458 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.05 · 1 PDB
Residue 189: a UniProt-annotated variant site (in cln1); a β-strand

Full PPT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronal ceroid lipofuscinosis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CLN1 disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

PPT1 p.Pro189Leu Uncertain significance ★ ⚠ same residue
PPT1 p.Pro189_Ile190insTer Likely pathogenic ★ same residue
PPT1 c.234+1G>A Pathogenic ★★ same condition
PPT1 c.362+1G>A Likely pathogenic ★★ same condition
PPT1 c.433+1G>A Pathogenic ★★ same condition
PPT1 c.627+1G>T Likely pathogenic ★★ same condition
PPT1 c.628-1G>T Pathogenic ★★ same condition
PPT1 c.628-2A>G Pathogenic/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/ppt1-p-pro189arg (accessed [today's date]).

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