Is CLN6 p.Arg62His (c.185G>A) pathogenic?

CLN6 p.Arg62His (c.185G>A) is classified Conflicting classifications of pathogenicity in CLN6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2023-11-03). AlphaMissense: likely pathogenic (0.9397); Very rare (popmax 0.0011%, sas); Associated with ceroid lipofuscinosis, neuronal, 6B (Kufs type).

What condition is associated with CLN6 p.Arg62His (c.185G>A)?

CLN6 p.Arg62His (c.185G>A) is associated with ceroid lipofuscinosis, neuronal, 6B (Kufs type), ceroid lipofuscinosis, neuronal, 6A, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN6 p.Arg62His (c.185G>A) in the general population?

CLN6 p.Arg62His (c.185G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CLN6 p.Arg62His (c.185G>A)?

AlphaMissense predicts likely pathogenic (score 0.9397) — an in-silico prediction, not a clinical call.

CLN6 p.Arg62His

c.185G>A · rs751486476 · VCV523022

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ceroid lipofuscinosis, neuronal, 6B (Kufs type)

Computational evidence

Protein change
AlphaMissense	0.9397	likely pathogenic
REVEL	0.956	strongly pathogenic-leaning
SaProt	LLR -9.56	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 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 21 kb · p 0.14 · regional, not allelic
Overall
CADD	32.0	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 0.0011% South Asian · 1/91,044 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000479% 7/1,460,644 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,044
European (non-Finnish)	0.000509%	196,497

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.Arg62His
Coding: c.185G>A
MANE Select: NM_017882
dbSNP: rs751486476
Type: single nucleotide variant
Location: chr15:68218549 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.86
Residue 62: a UniProt-annotated variant site (in cln6)

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

Disease context

ceroid lipofuscinosis, neuronal, 6B (Kufs type) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ceroid lipofuscinosis, neuronal, 6A neuronal ceroid lipofuscinosis

Similar variants

CLN6 p.Arg62Cys Likely pathogenic ★★ same residue
CLN6 p.Arg62fs 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

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-arg62his (accessed [today's date]).

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