Is CLN5 p.Trp330Cys (c.990G>T) pathogenic?

CLN5 p.Trp330Cys (c.990G>T) is classified Conflicting classifications of pathogenicity in CLN5 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-02-02). AlphaMissense: likely pathogenic (0.9891); Very rare (popmax 0.0023%, nfe); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN5 p.Trp330Cys (c.990G>T)?

CLN5 p.Trp330Cys (c.990G>T) is associated with neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 5 (ClinVar).

How common is CLN5 p.Trp330Cys (c.990G>T) in the general population?

CLN5 p.Trp330Cys (c.990G>T) is very rare (popmax 0.0023%, nfe) (gnomAD).

What do computational predictors say about CLN5 p.Trp330Cys (c.990G>T)?

AlphaMissense predicts likely pathogenic (score 0.9891) — an in-silico prediction, not a clinical call.

CLN5 p.Trp330Cys

c.990G>T · rs386833968 · VCV56530

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.9891	likely pathogenic · top 4% in CLN5
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -12.14	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 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 8,867 bp · p 0.55 · regional, not allelic
Overall
CADD	28.8	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 0.0023% European (non-Finnish) · 27/1,173,166 alleles

Filtering AF 0.00158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00182% 29/1,594,482 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0023%	43,451
Remaining individualsnot grpmax-eligible	0.00162%	61,616
African / African-American	0.00136%	73,590

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: CLN5
Protein: p.Trp330Cys
Coding: c.990G>T
MANE Select: NM_006493
dbSNP: rs386833968
Type: single nucleotide variant
Location: chr13:77000882 (GRCh38)
Gene constraint: LOEUF 1.197 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 1 PDB
Residue 330: a UniProt-annotated variant site (in cln5; retained in the endoplasmic reticulum rather than reaching the lysosome); the 'membrane-anchoring' region

Full CLN5 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

Also linked: neuronal ceroid lipofuscinosis 5

Similar variants

CLN5 p.Trp330Ter Pathogenic/Likely pathogenic ★★ same residue
CLN5 c.174-2A>G Likely pathogenic ★★ same condition
CLN5 p.Arg150Ter Pathogenic ★★ same condition
CLN5 p.Arg63His Pathogenic/Likely pathogenic ★★ ⚠ same condition
CLN5 p.Arg96Ter Pathogenic/Likely pathogenic ★★ same condition
CLN5 p.Asn143Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
CLN5 p.Cys144Tyr Pathogenic ★★ ⚠ same condition
CLN5 p.Cys77Tyr 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/cln5-p-trp330cys (accessed [today's date]).

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