Is CLN3 p.Arg334His (c.1001G>A) pathogenic?

CLN3 p.Arg334His (c.1001G>A) is classified Pathogenic/Likely pathogenic in CLN3 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.9536); Very rare (popmax 0.00203%, nfe); Associated with juvenile neuronal ceroid lipofuscinosis.

What condition is associated with CLN3 p.Arg334His (c.1001G>A)?

CLN3 p.Arg334His (c.1001G>A) is associated with juvenile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 3, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN3 p.Arg334His (c.1001G>A) in the general population?

CLN3 p.Arg334His (c.1001G>A) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about CLN3 p.Arg334His (c.1001G>A)?

AlphaMissense predicts likely pathogenic (score 0.9536) — an in-silico prediction, not a clinical call.

CLN3 p.Arg334His

c.1001G>A · rs386833695 · VCV56244

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

juvenile neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.9536	likely pathogenic ✓ concordant with ClinVar
REVEL	0.961	strongly pathogenic-leaning
SaProt	LLR -14.29	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 7.6	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 0.00203% European (non-Finnish) · 24/1,179,898 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00229% 37/1,613,402 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0172%	5,813
European (non-Finnish)grpmax	0.00203%	49,163
Admixed American	0.00167%	59,880
South Asian	0.0011%	90,974

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg334His
Coding: c.1001G>A
MANE Select: NM_001042432
dbSNP: rs386833695
Type: single nucleotide variant
Location: chr16:28482160 (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.Arg334Cys 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-arg334his (accessed [today's date]).

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