Is CLN8 p.Pro229Ala (c.685C>G) pathogenic?

CLN8 p.Pro229Ala (c.685C>G) is classified Benign in CLN8 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1253); Common (popmax 10.9%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with CLN8 p.Pro229Ala (c.685C>G)?

CLN8 p.Pro229Ala (c.685C>G) is associated with Inborn genetic diseases, central core myopathy, neuronal ceroid lipofuscinosis 8 (ClinVar).

What do computational predictors say about CLN8 p.Pro229Ala (c.685C>G)?

AlphaMissense predicts likely benign (score 0.1253) — an in-silico prediction, not a clinical call.

CLN8 p.Pro229Ala

Q: How common is CLN8 p.Pro229Ala (c.685C>G) in the general population?

CLN8 p.Pro229Ala (c.685C>G) is common (popmax 10.9%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.685C>G · rs150047904 · VCV95924

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.1253 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.9%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1253	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -7.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.8, phastCons 0.004
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	15.98	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 10.9% Admixed American · 6,555/60,016 alleles

Filtering AF 10.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.6%

Overall 0.428% 6,904/1,614,224 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	10.9%	9
Remaining individualsnot grpmax-eligible	0.277%	361
African / African-American	0.121%	825
South Asian	0.0285%	3,503
European (non-Finnish)	0.005%	20,001

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.Pro229Ala
Coding: c.685C>G
MANE Select: NM_018941
dbSNP: rs150047904
Type: single nucleotide variant
Location: chr8:1780391 (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 229: a UniProt-annotated variant site (in); the tlc domain

Full CLN8 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: central core myopathy neuronal ceroid lipofuscinosis 8 neuronal ceroid lipofuscinosis

Similar variants

CLN8 p.Pro229Leu Uncertain significance ★ ⚠ 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
CLN8 p.Gln99Ter 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-pro229ala (accessed [today's date]).

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