Is CLN8 p.Asn259Ser (c.776A>G) pathogenic?

CLN8 p.Asn259Ser (c.776A>G) is classified Conflicting classifications of pathogenicity in CLN8 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.0787); Ultra-rare (popmax 0.0217%, amr); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN8 p.Asn259Ser (c.776A>G)?

CLN8 p.Asn259Ser (c.776A>G) is associated with neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 8 (ClinVar).

How common is CLN8 p.Asn259Ser (c.776A>G) in the general population?

CLN8 p.Asn259Ser (c.776A>G) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about CLN8 p.Asn259Ser (c.776A>G)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

CLN8 p.Asn259Ser

c.776A>G · rs201956727 · VCV205210

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -8.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.5
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	0.086	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 0.0217% Admixed American · 13/60,004 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00279% 45/1,614,080 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,616
African / African-American	0.00534%	18,732
Remaining individualsnot grpmax-eligible	0.0032%	31,245
East Asian	0.00223%	44,882
European (non-Finnish)	0.00203%	49,169
South Asian	0.0011%	91,092

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.Asn259Ser
Coding: c.776A>G
MANE Select: NM_018941
dbSNP: rs201956727
Type: single nucleotide variant
Location: chr8:1780482 (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 259: the tlc domain

Full CLN8 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

Also linked: neuronal ceroid lipofuscinosis 8

Similar variants

CLN8 p.Asn259Asp Uncertain significance ★★ ⚠ same residue
CLN8 p.Asn259= Benign/Likely benign ★★ same residue
CLN8 p.Asn259Ile Uncertain significance ★ ⚠ same residue
CLN8 p.Asn259Thr 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

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-asn259ser (accessed [today's date]).

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