Is CLN8 p.Ala96= (c.288G>A) pathogenic?

CLN8 p.Ala96= (c.288G>A) is classified Likely benign in CLN8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-21). Ultra-rare (popmax 0.0165%, mid); Associated with neuronal ceroid lipofuscinosis 8 northern epilepsy variant.

What condition is associated with CLN8 p.Ala96= (c.288G>A)?

CLN8 p.Ala96= (c.288G>A) is associated with neuronal ceroid lipofuscinosis 8 northern epilepsy variant, neuronal ceroid lipofuscinosis 8, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN8 p.Ala96= (c.288G>A) in the general population?

CLN8 p.Ala96= (c.288G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is CLN8 disease inherited?

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

CLN8 p.Ala96=

c.288G>A · rs533351136 · VCV698746

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

neuronal ceroid lipofuscinosis 8 northern epilepsy variant

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 -12	GERP -4
Overall
CADD	0.155	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00142% 23/1,614,200 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.0133%	7,506
South Asian	0.00549%	18,217
East Asian	0.00446%	22,441
Admixed American	0.00167%	60,024
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000254%	393,345

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: CLN8
Protein: p.Ala96=
Coding: c.288G>A
MANE Select: NM_018941
dbSNP: rs533351136
Type: single nucleotide variant
Location: chr8:1771342 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB
Residue 96: the tlc domain

Full CLN8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronal ceroid lipofuscinosis 8 northern epilepsy variant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronal ceroid lipofuscinosis 8 neuronal ceroid lipofuscinosis

For CLN8 disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CLN8 p.Ala96Val Uncertain significance ★★ ⚠ same residue
CLN8 p.Arg204Cys Pathogenic/Likely pathogenic ★★ same condition
CLN8 p.Arg204His Likely pathogenic ★★ same condition
CLN8 p.Arg24Gly Pathogenic ★★ same condition
CLN8 p.Arg70Cys Pathogenic/Likely pathogenic ★★ same condition
CLN8 p.Arg70His Pathogenic/Likely pathogenic ★★ same condition
CLN8 p.Gln255Ter Pathogenic ★★ same condition
CLN8 p.Gln99Ter 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/cln8-p-ala96 (accessed [today's date]).

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