Is CLN3 p.Ser7Trp (c.20C>G) pathogenic?

CLN3 p.Ser7Trp (c.20C>G) is classified Uncertain significance in CLN3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-05-22). AlphaMissense: likely benign (0.1214); Very rare (popmax 8.47e-05%, nfe); Associated with juvenile neuronal ceroid lipofuscinosis.

What condition is associated with CLN3 p.Ser7Trp (c.20C>G)?

CLN3 p.Ser7Trp (c.20C>G) is associated with juvenile neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN3 p.Ser7Trp (c.20C>G) in the general population?

CLN3 p.Ser7Trp (c.20C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CLN3 p.Ser7Trp (c.20C>G)?

AlphaMissense predicts likely benign (score 0.1214) — an in-silico prediction, not a clinical call.

CLN3 p.Ser7Trp

c.20C>G · VCV4064811

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1214 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

juvenile neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.1214	likely benign
REVEL	0.333	indeterminate
SaProt	LLR -8.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.48, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 14 kb · p 0.08 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.84e-05% 1/1,461,696 alleles · very rare

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.Ser7Trp
Coding: c.20C>G
MANE Select: NM_001042432
Type: single nucleotide variant
Location: chr16:28491740 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.81
Residue 7: the 'disordered' region

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

Similar variants

CLN3 p.Ser7= Likely benign ★ same residue
CLN3 c.1197+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.222+1G>A Likely pathogenic ★★ same condition
CLN3 c.46+1G>A Likely pathogenic ★★ same condition
CLN3 c.461-2A>G Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.533+1G>C Pathogenic ★★ same condition
CLN3 c.534-2A>G Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.678-2A>G 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-ser7trp (accessed [today's date]).

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