Is CLN8 p.Arg97His (c.290G>A) pathogenic?

CLN8 p.Arg97His (c.290G>A) is classified Benign/Likely benign in CLN8 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0737); Rare (popmax 0.801%, afr); Associated with Inborn genetic diseases.

What condition is associated with CLN8 p.Arg97His (c.290G>A)?

CLN8 p.Arg97His (c.290G>A) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN8 p.Arg97His (c.290G>A) in the general population?

CLN8 p.Arg97His (c.290G>A) is rare (popmax 0.801%, afr) (gnomAD).

What do computational predictors say about CLN8 p.Arg97His (c.290G>A)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

CLN8 p.Arg97His

c.290G>A · rs116605307 · VCV136807

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.801%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -5.17	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 -4.2	GERP -4
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	1.062	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 0.801% African / African-American · 601/75,046 alleles

Filtering AF 0.748% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.727%

Overall 0.0476% 768/1,614,204 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.801%	125
Remaining individualsnot grpmax-eligible	0.0704%	1,421
East Asian	0.0557%	1,796
Admixed American	0.0466%	2,144
Middle Eastern	0.033%	3,030
European (non-Finnish)	0.00542%	18,438
South Asian	0.00439%	22,772

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.Arg97His
Coding: c.290G>A
MANE Select: NM_018941
dbSNP: rs116605307
Type: single nucleotide variant
Location: chr8:1771344 (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 97: 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: neuronal ceroid lipofuscinosis

Similar variants

CLN8 p.Arg97Cys Uncertain significance ★ ⚠ same residue
CLN8 p.Arg97Leu Uncertain significance ★ ⚠ same residue
CLN8 p.Arg97Ser Uncertain significance ★ ⚠ same residue
CLN8 p.Arg97= 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

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-arg97his (accessed [today's date]).

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