Is CLN6 p.Val91fs (c.268_271dup) pathogenic?

CLN6 p.Val91fs (c.268271dup) is classified Pathogenic in CLN6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-03). Very rare (popmax 0.000254%, nfe); Associated with CLN6-related disorder.

What condition is associated with CLN6 p.Val91fs (c.268_271dup)?

CLN6 p.Val91fs (c.268_271dup) is associated with CLN6-related disorder, ceroid lipofuscinosis, neuronal, 6A, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN6 p.Val91fs (c.268_271dup) in the general population?

CLN6 p.Val91fs (c.268_271dup) is very rare (popmax 0.000254%, nfe) (gnomAD).

CLN6 p.Val91fs

c.268_271dup · rs786205067 · VCV4086

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

CLN6-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.3	GERP 0.48, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,798 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,590 alleles · very 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: CLN6
Protein: p.Val91fs
Coding: c.268_271dup
MANE Select: NM_017882
dbSNP: rs786205067
Type: Duplication
Location: chr15:68214315 (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

CLN6-related disorder

Also linked: ceroid lipofuscinosis, neuronal, 6A neuronal ceroid lipofuscinosis

Similar variants

CLN6 p.Val91Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
CLN6 p.Arg106fs Pathogenic ★★ same condition
CLN6 p.Glu167Ter Pathogenic/Likely pathogenic ★★ same condition
CLN6 p.Val133fs Pathogenic/Likely pathogenic ★★ same condition
CLN6 c.83+14dup Benign/Likely benign ★★ same condition
CLN6 p.Asp83fs Pathogenic ★ same condition
CLN6 p.Gly61fs Pathogenic ★ same condition
CLN6 p.Leu97fs 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-val91fs (accessed [today's date]).

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