Is CLN6 p.Phe85Leu (c.255C>G) pathogenic?

CLN6 p.Phe85Leu (c.255C>G) is classified Uncertain significance in CLN6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-12). AlphaMissense: likely pathogenic (0.6844); Very rare (popmax 0.00891%, eas); Associated with ceroid lipofuscinosis, neuronal, 6B (Kufs type).

What condition is associated with CLN6 p.Phe85Leu (c.255C>G)?

CLN6 p.Phe85Leu (c.255C>G) is associated with ceroid lipofuscinosis, neuronal, 6B (Kufs type), ceroid lipofuscinosis, neuronal, 6A, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN6 p.Phe85Leu (c.255C>G) in the general population?

CLN6 p.Phe85Leu (c.255C>G) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about CLN6 p.Phe85Leu (c.255C>G)?

AlphaMissense predicts likely pathogenic (score 0.6844) — an in-silico prediction, not a clinical call.

CLN6 p.Phe85Leu

c.255C>G · rs545955828 · VCV205162

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ceroid lipofuscinosis, neuronal, 6B (Kufs type)

Computational evidence

Protein change
AlphaMissense	0.6844	likely pathogenic
REVEL	0.634	indeterminate
SaProt	LLR -6.56	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.54, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 21 kb · p 0.14 · regional, not allelic
Overall
CADD	21.7	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 0.00891% East Asian · 4/44,880 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000929% 15/1,614,142 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,220
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)	0.000847%	117,995

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.Phe85Leu
Coding: c.255C>G
MANE Select: NM_017882
dbSNP: rs545955828
Type: single nucleotide variant
Location: chr15:68214332 (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, 6B (Kufs type) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

CLN6 p.Phe85= Likely benign ★ same residue
CLN6 p.Phe85Cys Uncertain significance ★ 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-phe85leu (accessed [today's date]).

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