Is CLN5 p.Pro349Ser (c.1045C>T) pathogenic?

CLN5 p.Pro349Ser (c.1045C>T) is classified Uncertain significance in CLN5 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-10-30). AlphaMissense: likely pathogenic (0.6104); Ultra-rare (popmax 0.0214%, nfe); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN5 p.Pro349Ser (c.1045C>T)?

CLN5 p.Pro349Ser (c.1045C>T) is associated with neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 5 (ClinVar).

How common is CLN5 p.Pro349Ser (c.1045C>T) in the general population?

CLN5 p.Pro349Ser (c.1045C>T) is ultra-rare (popmax 0.0214%, nfe) (gnomAD).

What do computational predictors say about CLN5 p.Pro349Ser (c.1045C>T)?

AlphaMissense predicts likely pathogenic (score 0.6104) — an in-silico prediction, not a clinical call.

CLN5 p.Pro349Ser

c.1045C>T · rs41287036 · VCV128780

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.6104 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.6104	likely pathogenic
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -11.90	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 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 8,867 bp · p 0.55 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0214% European (non-Finnish) · 252/1,175,898 alleles

Filtering AF 0.0192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0173% 277/1,604,766 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.86%	54
European (non-Finnish)grpmax	0.0214%	4,666
African / African-American	0.00536%	18,671
Remaining individualsnot grpmax-eligible	0.00482%	20,750
Admixed American	0.00169%	59,310

Amish 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: CLN5
Protein: p.Pro349Ser
Coding: c.1045C>T
MANE Select: NM_006493
dbSNP: rs41287036
Type: single nucleotide variant
Location: chr13:77000937 (GRCh38)
Gene constraint: LOEUF 1.197 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 1 PDB

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.Pro349= Likely benign ★ 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-pro349ser (accessed [today's date]).

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