Is CLN6 p.Asp256Glu (c.768C>G) pathogenic?

CLN6 p.Asp256Glu (c.768C>G) is classified Pathogenic/Likely pathogenic in CLN6 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.9574); Very rare (popmax 0.00659%, sas); Associated with ceroid lipofuscinosis, neuronal, 6A.

What condition is associated with CLN6 p.Asp256Glu (c.768C>G)?

CLN6 p.Asp256Glu (c.768C>G) is associated with ceroid lipofuscinosis, neuronal, 6A, ceroid lipofuscinosis, neuronal, 6B (Kufs type), neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN6 p.Asp256Glu (c.768C>G) in the general population?

CLN6 p.Asp256Glu (c.768C>G) is very rare (popmax 0.00659%, sas) (gnomAD).

How is CLN6 disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CLN6 p.Asp256Glu (c.768C>G)?

AlphaMissense predicts likely pathogenic (score 0.9574) — an in-silico prediction, not a clinical call.

CLN6 p.Asp256Glu

c.768C>G · rs760271120 · VCV1072427

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ceroid lipofuscinosis, neuronal, 6A

Computational evidence

Protein change
AlphaMissense	0.9574	likely pathogenic ✓ concordant with ClinVar
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -8.98	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 21 kb · p 0.14 · regional, not allelic
Overall
CADD	26.9	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 0.00659% South Asian · 6/91,092 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000479% 7/1,461,806 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,182
European (non-Finnish)	8.47e-05%	1,180,050

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: CLN6
Protein: p.Asp256Glu
Coding: c.768C>G
MANE Select: NM_017882
dbSNP: rs760271120
Type: single nucleotide variant
Location: chr15:68208308 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.86

Full CLN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ceroid lipofuscinosis, neuronal, 6A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ceroid lipofuscinosis, neuronal, 6B (Kufs type)neuronal ceroid lipofuscinosis

For CLN6 disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CLN6 p.Asp256Gly Pathogenic/Likely pathogenic ★★ same residue
CLN6 p.Asp256fs Likely pathogenic same residue
CLN6 c.297+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN6 c.486+1G>A Likely pathogenic ★★ same condition
CLN6 c.543-1G>A Likely pathogenic ★★ same condition
CLN6 c.665+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN6 c.665+1G>T Likely pathogenic ★★ same condition
CLN6 c.83+1G>C 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/cln6-p-asp256glu (accessed [today's date]).

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