Is CLN3 p.Ser423Ter (c.1268C>A) pathogenic?

CLN3 p.Ser423Ter (c.1268C>A) is classified Likely pathogenic in CLN3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-01-23). Absent from gnomAD v4.1; Associated with neuronal ceroid lipofuscinosis 3.

What condition is associated with CLN3 p.Ser423Ter (c.1268C>A)?

CLN3 p.Ser423Ter (c.1268C>A) is associated with neuronal ceroid lipofuscinosis 3 (ClinVar).

How common is CLN3 p.Ser423Ter (c.1268C>A) in the general population?

CLN3 p.Ser423Ter (c.1268C>A) is absent from gnomAD v4.1 (gnomAD).

How is CLN3 disease inherited?

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

CLN3 p.Ser423Ter

c.1268C>A · rs386833706 · VCV56255

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

neuronal ceroid lipofuscinosis 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (16 of 16) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	Δ0.38	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 0.15, phastCons 1
Overall
CADD	45.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLN3
Protein: p.Ser423Ter
Coding: c.1268C>A
MANE Select: NM_001042432
dbSNP: rs386833706
Type: single nucleotide variant
Location: chr16:28477565 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.81

Full CLN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronal ceroid lipofuscinosis 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CLN3 disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CLN3 p.Ser423Leu Uncertain significance ★★ ⚠ same residue
CLN3 p.Ser423= Likely benign ★★ same residue
CLN3 c.1056+3A>C Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.1197+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.1198-1G>T Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.125+1G>C Pathogenic ★★ same condition
CLN3 c.46+1G>A Likely pathogenic ★★ same condition
CLN3 c.461-1G>T Pathogenic/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/cln3-p-ser423ter (accessed [today's date]).

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