Is CLN8 p.Met1Val (c.1A>G) pathogenic?

CLN8 p.Met1Val (c.1A>G) is classified Pathogenic/Likely pathogenic in CLN8 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-04). Very rare (popmax 0.00446%, eas); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN8 p.Met1Val (c.1A>G)?

CLN8 p.Met1Val (c.1A>G) is associated with neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 8 (ClinVar).

How common is CLN8 p.Met1Val (c.1A>G) in the general population?

CLN8 p.Met1Val (c.1A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

CLN8 p.Met1Val

c.1A>G · rs143730802 · VCV487522

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.671	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 2, phastCons 1
Overall
CADD	17.47	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,848 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000991% 16/1,614,086 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,424
African / African-American	0.00133%	75,028
European (non-Finnish)	0.0011%	90,771

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.Met1Val
Coding: c.1A>G
MANE Select: NM_018941
dbSNP: rs143730802
Type: single nucleotide variant
Location: chr8:1771055 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB

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.Met1Leu Pathogenic ★ same residue
CLN8 p.Met1Thr Likely pathogenic same residue
CLN8 p.Met1* Pathogenic ★ 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

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-met1val (accessed [today's date]).

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