Is CLN3 p.Arg334Cys (c.1000C>T) pathogenic?

CLN3 p.Arg334Cys (c.1000C>T) is classified Pathogenic/Likely pathogenic in CLN3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-09-17). AlphaMissense: likely pathogenic (0.8927); Very rare (popmax 0.0011%, sas); Associated with juvenile neuronal ceroid lipofuscinosis.

What condition is associated with CLN3 p.Arg334Cys (c.1000C>T)?

CLN3 p.Arg334Cys (c.1000C>T) is associated with juvenile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 3, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN3 p.Arg334Cys (c.1000C>T) in the general population?

CLN3 p.Arg334Cys (c.1000C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CLN3 p.Arg334Cys (c.1000C>T)?

AlphaMissense predicts likely pathogenic (score 0.8927) — an in-silico prediction, not a clinical call.

CLN3 p.Arg334Cys

c.1000C>T · rs386833694 · VCV56243

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.8927 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

juvenile neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.8927	likely pathogenic ✓ concordant with ClinVar
REVEL	0.992	strongly pathogenic-leaning
SaProt	LLR -12.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 14 kb · p 0.08 · regional, not allelic
Overall
CADD	33.0	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 0.0011% South Asian · 1/90,994 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000411% 6/1,461,512 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,994
European (non-Finnish)	0.000424%	235,980

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: CLN3
Protein: p.Arg334Cys
Coding: c.1000C>T
MANE Select: NM_001042432
dbSNP: rs386833694
Type: single nucleotide variant
Location: chr16:28482161 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.81
Residue 334: a UniProt-annotated variant site (in cln3; does not affect lysosomal localization. does not affect lysosomal protein catabolic process. does not affect lysosomal ph); a UniProt-annotated variant site (in cln3)

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

Disease context

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

Also linked: neuronal ceroid lipofuscinosis 3 neuronal ceroid lipofuscinosis

Similar variants

CLN3 p.Arg334His Pathogenic/Likely pathogenic ★★ same residue
CLN3 p.Arg334= Likely benign ★★ same residue
CLN3 c.1056+1G>A Likely pathogenic ★★ same condition
CLN3 c.1056+1G>T Likely pathogenic ★★ same condition
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

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-arg334cys (accessed [today's date]).

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