Is CLN8 p.Leu207Arg (c.620T>G) pathogenic?

CLN8 p.Leu207Arg (c.620T>G) is classified Likely pathogenic in CLN8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.9443); Ultra-rare (popmax 0.0111%, eas); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN8 p.Leu207Arg (c.620T>G)?

CLN8 p.Leu207Arg (c.620T>G) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN8 p.Leu207Arg (c.620T>G) in the general population?

CLN8 p.Leu207Arg (c.620T>G) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about CLN8 p.Leu207Arg (c.620T>G)?

AlphaMissense predicts likely pathogenic (score 0.9443) — an in-silico prediction, not a clinical call.

CLN8 p.Leu207Arg

c.620T>G · VCV3720796

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9443 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.9443	likely pathogenic ✓ concordant with ClinVar
REVEL	0.738	pathogenic-leaning
SaProt	LLR -11.16	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	27.1	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 0.0111% East Asian · 5/44,890 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000342% 5/1,461,888 alleles · ultra-rare

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.Leu207Arg
Coding: c.620T>G
MANE Select: NM_018941
Type: single nucleotide variant
Location: chr8:1780326 (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 207: a UniProt-annotated variant site (in cln8; uncertain significance); 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

Similar variants

CLN8 p.Leu207Val 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-leu207arg (accessed [today's date]).

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