Is CLN5 p.Ala2Val (c.5C>T) pathogenic?

CLN5 p.Ala2Val (c.5C>T) is classified Conflicting classifications of pathogenicity in CLN5 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.2873); Ultra-rare (popmax 0.034%, mid); Associated with Inborn genetic diseases.

What condition is associated with CLN5 p.Ala2Val (c.5C>T)?

CLN5 p.Ala2Val (c.5C>T) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis 5, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN5 p.Ala2Val (c.5C>T) in the general population?

CLN5 p.Ala2Val (c.5C>T) is ultra-rare (popmax 0.034%, mid) (gnomAD).

What do computational predictors say about CLN5 p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2873) — an in-silico prediction, not a clinical call.

CLN5 p.Ala2Val

c.5C>T · rs146993892 · VCV205125

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2873 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2873	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -7.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.33	GERP -0.79, phastCons 0.001
Regional constraint	o/e 0.97	unconstrained · MANE · 8,867 bp · p 0.55 · regional, not allelic
Overall
CADD	13.95	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 0.034% Middle Eastern · 2/5,890 alleles

Filtering AF 0.00868% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.0385% 620/1,611,760 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.36%	73
Remaining individualsnot grpmax-eligible	0.132%	760
Middle Easterngrpmax	0.034%	2,945
African / African-American	0.0107%	9,360
European (non-Finnish)	0.0102%	9,828
Admixed American	0.00834%	11,988
South Asian	0.0011%	91,018

Ashkenazi Jewish 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.Ala2Val
Coding: c.5C>T
MANE Select: NM_006493
dbSNP: rs146993892
Type: single nucleotide variant
Location: chr13:76992103 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronal ceroid lipofuscinosis 5 neuronal ceroid lipofuscinosis

Similar variants

CLN5 p.Ala2= Likely benign ★ same residue
CLN5 p.Arg2Pro 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

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-ala2val (accessed [today's date]).

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