Is CLN8 p.Ala182Thr (c.544G>A) pathogenic?

CLN8 p.Ala182Thr (c.544G>A) is classified Uncertain significance in CLN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.2323); Very rare (popmax 0.00329%, sas); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN8 p.Ala182Thr (c.544G>A)?

CLN8 p.Ala182Thr (c.544G>A) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN8 p.Ala182Thr (c.544G>A) in the general population?

CLN8 p.Ala182Thr (c.544G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about CLN8 p.Ala182Thr (c.544G>A)?

AlphaMissense predicts likely benign (score 0.2323) — an in-silico prediction, not a clinical call.

CLN8 p.Ala182Thr

c.544G>A · rs752847178 · VCV1904269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2323 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.2323	likely benign
REVEL	0.651	pathogenic-leaning
SaProt	LLR -6.92	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	23.9	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 0.00329% South Asian · 3/91,090 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000205% 3/1,461,892 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: CLN8
Protein: p.Ala182Thr
Coding: c.544G>A
MANE Select: NM_018941
dbSNP: rs752847178
Type: single nucleotide variant
Location: chr8:1780250 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB
Residue 182: the tlc domain

Full CLN8 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

Similar variants

CLN8 p.Ala182Val Uncertain significance ★★ ⚠ same residue
CLN8 p.Ala182= Likely benign ★ same residue
CLN8 p.Arg204Cys Pathogenic/Likely pathogenic ★★ same condition
CLN8 p.Arg204His Likely pathogenic ★★ same condition
CLN8 p.Arg24Gly Pathogenic ★★ same condition
CLN8 p.Arg70Cys Pathogenic/Likely pathogenic ★★ same condition
CLN8 p.Arg70His Pathogenic/Likely pathogenic ★★ same condition
CLN8 p.Gln255Ter 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/cln8-p-ala182thr (accessed [today's date]).

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