Is CLN6 p.Lys99Arg (c.296A>G) pathogenic?

CLN6 p.Lys99Arg (c.296A>G) is classified Conflicting classifications of pathogenicity in CLN6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-04-03). AlphaMissense: likely benign (0.1893); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with CLN6 p.Lys99Arg (c.296A>G)?

CLN6 p.Lys99Arg (c.296A>G) is associated with Inborn genetic diseases, ceroid lipofuscinosis, neuronal, 6B (Kufs type), ceroid lipofuscinosis, neuronal, 6A (ClinVar).

How common is CLN6 p.Lys99Arg (c.296A>G) in the general population?

CLN6 p.Lys99Arg (c.296A>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CLN6 p.Lys99Arg (c.296A>G)?

AlphaMissense predicts likely benign (score 0.1893) — an in-silico prediction, not a clinical call.

CLN6 p.Lys99Arg

c.296A>G · rs146782642 · VCV1184730

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1893	likely benign
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -6.25	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.78	donor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.58	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 21 kb · p 0.14 · regional, not allelic
Overall
CADD	28.1	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 0.00134% African / African-American · 1/74,860 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000745% 12/1,611,316 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,860
European (non-Finnish)	0.000934%	107,057

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.Lys99Arg
Coding: c.296A>G
MANE Select: NM_017882
dbSNP: rs146782642
Type: single nucleotide variant
Location: chr15:68214291 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.86

Full CLN6 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: ceroid lipofuscinosis, neuronal, 6B (Kufs type)ceroid lipofuscinosis, neuronal, 6A neuronal ceroid lipofuscinosis

Similar variants

CLN6 p.Lys99Asn Likely pathogenic ★★ 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
CLN6 c.84-1G>A 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/cln6-p-lys99arg (accessed [today's date]).

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