Is CLN8 p.Val175Ile (c.523G>A) pathogenic?

CLN8 p.Val175Ile (c.523G>A) is classified Conflicting classifications of pathogenicity in CLN8 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-26). AlphaMissense: likely benign (0.0618); Ultra-rare (popmax 0.0571%, sas); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN8 p.Val175Ile (c.523G>A)?

CLN8 p.Val175Ile (c.523G>A) is associated with neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 8 (ClinVar).

How common is CLN8 p.Val175Ile (c.523G>A) in the general population?

CLN8 p.Val175Ile (c.523G>A) is ultra-rare (popmax 0.0571%, sas) (gnomAD).

What do computational predictors say about CLN8 p.Val175Ile (c.523G>A)?

AlphaMissense predicts likely benign (score 0.0618) — an in-silico prediction, not a clinical call.

CLN8 p.Val175Ile

c.523G>A · rs768139689 · VCV848463

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0618 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0571%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.0618	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -5.97	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 -4.1	GERP -3.9
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	0.016	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 0.0571% South Asian · 52/91,086 alleles

Filtering AF 0.0447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0403%

Overall 0.00694% 112/1,613,802 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0571%	1,752
Middle Eastern	0.0329%	3,042
East Asian	0.0178%	5,610
Remaining individualsnot grpmax-eligible	0.0096%	10,414
African / African-American	0.00668%	14,976
Admixed American	0.00334%	29,984
European (non-Finnish)	0.00314%	31,892

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.Val175Ile
Coding: c.523G>A
MANE Select: NM_018941
dbSNP: rs768139689
Type: single nucleotide variant
Location: chr8:1771577 (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 175: 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

Also linked: neuronal ceroid lipofuscinosis 8

Similar variants

CLN8 p.Val175Leu 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-val175ile (accessed [today's date]).

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