Is PPT1 p.Val181= (c.543G>A) pathogenic?

PPT1 p.Val181= (c.543G>A) is classified Likely benign in PPT1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-05). Rare (popmax 0.115%, mid); Associated with neuronal ceroid lipofuscinosis 1.

What condition is associated with PPT1 p.Val181= (c.543G>A)?

PPT1 p.Val181= (c.543G>A) is associated with neuronal ceroid lipofuscinosis 1 (ClinVar).

How common is PPT1 p.Val181= (c.543G>A) in the general population?

PPT1 p.Val181= (c.543G>A) is rare (popmax 0.115%, mid) (gnomAD).

How is CLN1 disease inherited?

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

PPT1 p.Val181=

c.543G>A · rs374121503 · VCV516507

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Conditions

neuronal ceroid lipofuscinosis 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.51	GERP -1.7, phastCons 0.026
Overall
CADD	5.237	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% Middle Eastern · 7/6,082 alleles

Filtering AF 0.054% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.00508% 82/1,613,572 alleles · rare exomes 75/1,461,586 · genomes 7/151,986 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	869
Admixed American	0.0117%	8,567
Remaining individualsnot grpmax-eligible	0.00801%	12,492
European (non-Finnish)	0.00492%	20,342
South Asian	0.00329%	30,361
Finnishnot grpmax-eligible	0.00313%	31,973

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.Val181=
Coding: c.543G>A
MANE Select: NM_000310
dbSNP: rs374121503
Type: single nucleotide variant
Location: chr1:40080481 (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 181: a UniProt-annotated variant site (in cln1); a UniProt-annotated variant site (in cln1; late infantile form); an α-helix

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.Val181Leu Pathogenic/Likely pathogenic ★★ same residue
PPT1 p.Val181Met 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-val181 (accessed [today's date]).

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