Is CLN6 p.Ser33= (c.99C>T) pathogenic?

CLN6 p.Ser33= (c.99C>T) is classified Likely benign in CLN6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-14). Very rare (popmax 0.00446%, eas); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN6 p.Ser33= (c.99C>T)?

CLN6 p.Ser33= (c.99C>T) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN6 p.Ser33= (c.99C>T) in the general population?

CLN6 p.Ser33= (c.99C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

CLN6 p.Ser33=

c.99C>T · rs752449801 · VCV205151

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP -3, phastCons 0.029
Overall
CADD	7.197	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00217% 35/1,613,236 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
South Asian	0.00439%	22,763
European (non-Finnish)	0.00237%	42,129
Admixed American	0.00167%	59,976

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.Ser33=
Coding: c.99C>T
MANE Select: NM_017882
dbSNP: rs752449801
Type: single nucleotide variant
Location: chr15:68218635 (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

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

Similar variants

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.84-1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN6 p.Arg103Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
CLN6 p.Arg149Cys Likely pathogenic ★★ same condition
CLN6 p.Arg28Lys 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-ser33 (accessed [today's date]).

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