Is CLN3 p.Arg89Gln (c.266G>A) pathogenic?

CLN3 p.Arg89Gln (c.266G>A) is classified Conflicting classifications of pathogenicity in CLN3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2022-08-29). AlphaMissense: likely benign (0.0923); Ultra-rare (popmax 0.01%, amr); Associated with CLN3-related disorders.

What condition is associated with CLN3 p.Arg89Gln (c.266G>A)?

CLN3 p.Arg89Gln (c.266G>A) is associated with CLN3-related disorders, neuronal ceroid lipofuscinosis 3, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN3 p.Arg89Gln (c.266G>A) in the general population?

CLN3 p.Arg89Gln (c.266G>A) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about CLN3 p.Arg89Gln (c.266G>A)?

AlphaMissense predicts likely benign (score 0.0923) — an in-silico prediction, not a clinical call.

CLN3 p.Arg89Gln

c.266G>A · rs766287694 · VCV205106

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0923 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CLN3-related disorders

Computational evidence

Protein change
AlphaMissense	0.0923	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 14 kb · p 0.08 · regional, not allelic
Overall
CADD	25.4	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 0.01% Admixed American · 6/59,988 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000434% 7/1,614,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,998
European (non-Finnish)	8.47e-05%	1,180,036

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: CLN3
Protein: p.Arg89Gln
Coding: c.266G>A
MANE Select: NM_001042432
dbSNP: rs766287694
Type: single nucleotide variant
Location: chr16:28488619 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.81

Full CLN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CLN3-related disorders

Also linked: neuronal ceroid lipofuscinosis 3 neuronal ceroid lipofuscinosis

Similar variants

CLN3 p.Arg89Ter Pathogenic/Likely pathogenic ★★ same residue
CLN3 p.Arg89Leu Uncertain significance ★ ⚠ same residue
CLN3 c.1056+1G>A Likely pathogenic ★★ same condition
CLN3 c.1056+1G>T Likely pathogenic ★★ same condition
CLN3 c.1056+3A>C Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.1197+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.1198-1G>T Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.125+1G>C 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/cln3-p-arg89gln (accessed [today's date]).

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