Is CLN8 p.Glu269Val (c.806A>T) pathogenic?

CLN8 p.Glu269Val (c.806A>T) is classified Conflicting classifications of pathogenicity in CLN8 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.1162); Low-frequency (popmax 1.12%, mid); Associated with Inborn genetic diseases.

What condition is associated with CLN8 p.Glu269Val (c.806A>T)?

CLN8 p.Glu269Val (c.806A>T) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis 8, neuronal ceroid lipofuscinosis 8 northern epilepsy variant (ClinVar).

How common is CLN8 p.Glu269Val (c.806A>T) in the general population?

CLN8 p.Glu269Val (c.806A>T) is low-frequency (popmax 1.12%, mid) (gnomAD).

What do computational predictors say about CLN8 p.Glu269Val (c.806A>T)?

AlphaMissense predicts likely benign (score 0.1162) — an in-silico prediction, not a clinical call.

CLN8 p.Glu269Val

c.806A>T · rs139003032 · VCV196493

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.1162 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.12%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1162	likely benign
REVEL	0.559	indeterminate
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP -0.5, phastCons 0.008
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	13.33	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 1.12% Middle Eastern · 68/6,062 alleles

Filtering AF 0.908% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.83%

Overall 0.0247% 399/1,614,244 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.12%	89
Admixed American	0.065%	1,539
South Asian	0.0637%	1,570
Remaining individualsnot grpmax-eligible	0.0464%	2,155
European (non-Finnish)	0.0163%	6,146
African / African-American	0.0147%	6,825
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Finnishnot grpmax-eligible	0.00156%	64,040

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.Glu269Val
Coding: c.806A>T
MANE Select: NM_018941
dbSNP: rs139003032
Type: single nucleotide variant
Location: chr8:1780512 (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 269: a UniProt-annotated variant site (in cln8)

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.Glu269Gly Uncertain significance ★★ ⚠ same residue
CLN8 p.Glu269Lys 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

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-glu269val (accessed [today's date]).

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