Is CLN8 p.Gln76Pro (c.227A>C) pathogenic?

CLN8 p.Gln76Pro (c.227A>C) is classified Uncertain significance in CLN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-15). AlphaMissense: likely pathogenic (0.6838); Very rare (popmax 0.000254%, nfe); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN8 p.Gln76Pro (c.227A>C)?

CLN8 p.Gln76Pro (c.227A>C) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN8 p.Gln76Pro (c.227A>C) in the general population?

CLN8 p.Gln76Pro (c.227A>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CLN8 p.Gln76Pro (c.227A>C)?

AlphaMissense predicts likely pathogenic (score 0.6838) — an in-silico prediction, not a clinical call.

CLN8 p.Gln76Pro

c.227A>C · rs386834125 · VCV1909953

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6838 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.6838	likely pathogenic
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -8.42	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	26.1	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 0.000254% European (non-Finnish) · 3/1,180,006 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,864 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.Gln76Pro
Coding: c.227A>C
MANE Select: NM_018941
dbSNP: rs386834125
Type: single nucleotide variant
Location: chr8:1771281 (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 76: a UniProt-annotated variant site (in cln8); 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.Gln76Ter Pathogenic ★ same residue
CLN8 p.Gln76= Likely benign ★ same residue
CLN8 p.Gln76Arg Likely pathogenic 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

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-gln76pro (accessed [today's date]).

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