Is CLN8 p.Pro171Thr (c.511C>A) pathogenic?

CLN8 p.Pro171Thr (c.511C>A) is classified Uncertain significance in CLN8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-01-28). AlphaMissense: likely pathogenic (0.8221); Very rare (popmax 0.00133%, afr); Associated with neuronal ceroid lipofuscinosis 8.

What condition is associated with CLN8 p.Pro171Thr (c.511C>A)?

CLN8 p.Pro171Thr (c.511C>A) is associated with neuronal ceroid lipofuscinosis 8 (ClinVar).

How common is CLN8 p.Pro171Thr (c.511C>A) in the general population?

CLN8 p.Pro171Thr (c.511C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

How is CLN8 disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CLN8 p.Pro171Thr (c.511C>A)?

AlphaMissense predicts likely pathogenic (score 0.8221) — an in-silico prediction, not a clinical call.

CLN8 p.Pro171Thr

c.511C>A · VCV4064856

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8221 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 8

Computational evidence

Protein change
AlphaMissense	0.8221	likely pathogenic
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -12.27	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 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	26.5	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 0.00133% African / African-American · 1/75,026 alleles

Overall 0.000137% 2/1,461,826 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,026
South Asian	0.0011%	91,076

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.Pro171Thr
Coding: c.511C>A
MANE Select: NM_018941
Type: single nucleotide variant
Location: chr8:1771565 (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 171: the tlc domain

Full CLN8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronal ceroid lipofuscinosis 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CLN8 disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CLN8 p.Pro171Arg Uncertain significance ★★ ⚠ same residue
CLN8 p.Pro171= 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-pro171thr (accessed [today's date]).

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