Is CLN8 p.Ala4Val (c.11C>T) pathogenic?

CLN8 p.Ala4Val (c.11C>T) is classified Conflicting classifications of pathogenicity in CLN8 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.0699); Rare (popmax 0.549%, afr); Associated with Inborn genetic diseases.

What condition is associated with CLN8 p.Ala4Val (c.11C>T)?

CLN8 p.Ala4Val (c.11C>T) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis 8, neuronal ceroid lipofuscinosis 8 northern epilepsy variant (ClinVar).

How common is CLN8 p.Ala4Val (c.11C>T) in the general population?

CLN8 p.Ala4Val (c.11C>T) is rare (popmax 0.549%, afr) (gnomAD).

What do computational predictors say about CLN8 p.Ala4Val (c.11C>T)?

AlphaMissense predicts likely benign (score 0.0699) — an in-silico prediction, not a clinical call.

CLN8 p.Ala4Val

c.11C>T · rs147181589 · VCV195348

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0699 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.549%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0699	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -6.60	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 -4.5	GERP -4
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	0.009	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 0.549% African / African-American · 412/75,008 alleles

Filtering AF 0.505% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.488%

Overall 0.0363% 586/1,613,978 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.549%	182
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.0448%	2,232
Admixed American	0.0433%	2,308
European (non-Finnish)	0.00932%	10,727
South Asian	0.00549%	18,215

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.Ala4Val
Coding: c.11C>T
MANE Select: NM_018941
dbSNP: rs147181589
Type: single nucleotide variant
Location: chr8:1771065 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronal ceroid lipofuscinosis 8 neuronal ceroid lipofuscinosis 8 northern epilepsy variant neuronal ceroid lipofuscinosis

Similar variants

CLN8 p.Ala4= Likely benign ★ 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-ala4val (accessed [today's date]).

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