Is CLN6 p.Arg103Trp (c.307C>T) pathogenic?

CLN6 p.Arg103Trp (c.307C>T) is classified Conflicting classifications of pathogenicity in CLN6 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-19). AlphaMissense: likely pathogenic (0.7036); Ultra-rare (popmax 0.029%, eas); Associated with CLN6-related disorder.

What condition is associated with CLN6 p.Arg103Trp (c.307C>T)?

CLN6 p.Arg103Trp (c.307C>T) is associated with CLN6-related disorder, ceroid lipofuscinosis, neuronal, 6B (Kufs type), ceroid lipofuscinosis, neuronal, 6A (ClinVar).

How common is CLN6 p.Arg103Trp (c.307C>T) in the general population?

CLN6 p.Arg103Trp (c.307C>T) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about CLN6 p.Arg103Trp (c.307C>T)?

AlphaMissense predicts likely pathogenic (score 0.7036) — an in-silico prediction, not a clinical call.

CLN6 p.Arg103Trp

c.307C>T · rs201095412 · VCV498240

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7036 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CLN6-related disorder

Computational evidence

Protein change
AlphaMissense	0.7036	likely pathogenic
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -9.48	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 0.33, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 21 kb · p 0.14 · regional, not allelic
Overall
CADD	27.7	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 0.029% East Asian · 13/44,876 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00161% 26/1,613,470 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,452
Remaining individualsnot grpmax-eligible	0.0032%	31,240
Admixed American	0.00167%	60,016
South Asian	0.0011%	91,066
European (non-Finnish)	0.000763%	131,105

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: CLN6
Protein: p.Arg103Trp
Coding: c.307C>T
MANE Select: NM_017882
dbSNP: rs201095412
Type: single nucleotide variant
Location: chr15:68211854 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.86
Residue 103: a UniProt-annotated variant site (in cln4a)

Full CLN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CLN6-related disorder

Also linked: ceroid lipofuscinosis, neuronal, 6B (Kufs type)ceroid lipofuscinosis, neuronal, 6A neuronal ceroid lipofuscinosis

Similar variants

CLN6 p.Arg103Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
CLN6 p.Arg103= Likely benign ★ same residue
CLN6 c.297+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN6 c.486+1G>A Likely pathogenic ★★ same condition
CLN6 c.543-1G>A Likely pathogenic ★★ same condition
CLN6 c.665+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN6 c.665+1G>T Likely pathogenic ★★ same condition
CLN6 c.83+1G>C 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/cln6-p-arg103trp (accessed [today's date]).

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