Is CLN8 p.Arg70Cys (c.208C>T) pathogenic?

CLN8 p.Arg70Cys (c.208C>T) is classified Pathogenic/Likely pathogenic in CLN8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-03-26). AlphaMissense: likely pathogenic (0.8985); Very rare (popmax 0.00133%, afr); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN8 p.Arg70Cys (c.208C>T)?

CLN8 p.Arg70Cys (c.208C>T) is associated with neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 8 (ClinVar).

How common is CLN8 p.Arg70Cys (c.208C>T) in the general population?

CLN8 p.Arg70Cys (c.208C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CLN8 p.Arg70Cys (c.208C>T)?

AlphaMissense predicts likely pathogenic (score 0.8985) — an in-silico prediction, not a clinical call.

CLN8 p.Arg70Cys

c.208C>T · rs765097897 · VCV242453

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8985 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.8985	likely pathogenic ✓ concordant with ClinVar
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -10.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 2, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	32.0	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 0.00133% African / African-American · 1/75,024 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00116% 17/1,461,512 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,024
European (non-Finnish)	0.00127%	78,647
South Asian	0.0011%	91,062

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.Arg70Cys
Coding: c.208C>T
MANE Select: NM_018941
dbSNP: rs765097897
Type: single nucleotide variant
Location: chr8:1771262 (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 70: a UniProt-annotated variant site (in cln8); 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.Arg70His Pathogenic/Likely pathogenic ★★ same residue
CLN8 p.Arg70Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
CLN8 p.Arg70= Likely benign ★ same residue
CLN8 p.Arg70Leu 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.Gln255Ter 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-arg70cys (accessed [today's date]).

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