Is CLN3 p.Pro259= (c.777G>A) pathogenic?

CLN3 p.Pro259= (c.777G>A) is classified Likely benign in CLN3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-02-25). Ultra-rare (popmax 0.0313%, eas); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN3 p.Pro259= (c.777G>A)?

CLN3 p.Pro259= (c.777G>A) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN3 p.Pro259= (c.777G>A) in the general population?

CLN3 p.Pro259= (c.777G>A) is ultra-rare (popmax 0.0313%, eas) (gnomAD).

CLN3 p.Pro259=

c.777G>A · rs751443804 · VCV389056

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0313%, eas)

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 -5	GERP -2.7
Overall
CADD	3.622	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0313% East Asian · 14/44,774 alleles

Filtering AF 0.0189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00149% 24/1,609,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0313%	3,198
Admixed American	0.00337%	29,659
South Asian	0.00111%	89,900
European (non-Finnish)	0.000594%	168,252

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.Pro259=
Coding: c.777G>A
MANE Select: NM_001042432
dbSNP: rs751443804
Type: single nucleotide variant
Location: chr16:28484019 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.81
Residue 259: 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.Pro259Gln Uncertain significance ★ ⚠ same residue
CLN3 p.Pro259Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CLN3 p.Pro259Ser 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

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-pro259 (accessed [today's date]).

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