Is CLN8 p.Arg204His (c.611G>A) pathogenic?

CLN8 p.Arg204His (c.611G>A) is classified Likely pathogenic in CLN8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-09). AlphaMissense: likely pathogenic (0.9258); Very rare (popmax 0.00223%, eas); Associated with CLN8-related disorder.

What condition is associated with CLN8 p.Arg204His (c.611G>A)?

CLN8 p.Arg204His (c.611G>A) is associated with CLN8-related disorder, neuronal ceroid lipofuscinosis 8, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN8 p.Arg204His (c.611G>A) in the general population?

CLN8 p.Arg204His (c.611G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CLN8 p.Arg204His (c.611G>A)?

AlphaMissense predicts likely pathogenic (score 0.9258) — an in-silico prediction, not a clinical call.

CLN8 p.Arg204His

c.611G>A · rs386834134 · VCV557767

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CLN8-related disorder

Computational evidence

Protein change
AlphaMissense	0.9258	likely pathogenic ✓ concordant with ClinVar
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -10.45	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	29.7	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 0.00223% East Asian · 1/44,902 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.00031% 5/1,614,118 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,902
South Asian	0.0022%	45,546
Admixed American	0.00167%	60,002
European (non-Finnish)	8.47e-05%	1,180,058

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.Arg204His
Coding: c.611G>A
MANE Select: NM_018941
dbSNP: rs386834134
Type: single nucleotide variant
Location: chr8:1780317 (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 204: 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

CLN8-related disorder

Also linked: neuronal ceroid lipofuscinosis 8 neuronal ceroid lipofuscinosis

Similar variants

CLN8 p.Arg204Cys Pathogenic/Likely pathogenic ★★ same residue
CLN8 p.Arg204Gly Likely pathogenic ★ same residue
CLN8 p.Arg204Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CLN8 p.Arg204= Likely benign ★ same residue
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

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-arg204his (accessed [today's date]).

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