Is CLN3 p.Pro252= (c.756C>T) pathogenic?

CLN3 p.Pro252= (c.756C>T) is classified Likely benign in CLN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). Very rare (popmax 0.00133%, afr); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN3 p.Pro252= (c.756C>T)?

CLN3 p.Pro252= (c.756C>T) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN3 p.Pro252= (c.756C>T) in the general population?

CLN3 p.Pro252= (c.756C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

CLN3 p.Pro252=

c.756C>T · rs2046158184 · VCV1152286

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

neuronal ceroid lipofuscinosis

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 -0.004	GERP -2.7, phastCons 0.029
Overall
CADD	2.423	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,992 alleles

Overall 6.2e-05% 1/1,611,932 alleles · very rare exomes 1/1,459,704 · genomes 0/152,228 · 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: CLN3
Protein: p.Pro252=
Coding: c.756C>T
MANE Select: NM_001042432
dbSNP: rs2046158184
Type: single nucleotide variant
Location: chr16:28484040 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.81
Residue 252: the 'disordered' region

Full CLN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

CLN3 p.Pro252Ser Uncertain significance ★★ ⚠ same residue
CLN3 p.Pro252Leu Uncertain significance ★ ⚠ same residue
CLN3 c.1056+1G>A Likely pathogenic ★★ same condition
CLN3 c.1056+1G>T Likely pathogenic ★★ same condition
CLN3 c.1056+3A>C Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.1197+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.1198-1G>T Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.125+1G>C 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/cln3-p-pro252 (accessed [today's date]).

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