Is CLN6 p.Ala274= (c.822G>A) pathogenic?

CLN6 p.Ala274= (c.822G>A) is classified Conflicting classifications of pathogenicity in CLN6 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-26). Rare (popmax 0.117%, sas); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN6 p.Ala274= (c.822G>A)?

CLN6 p.Ala274= (c.822G>A) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN6 p.Ala274= (c.822G>A) in the general population?

CLN6 p.Ala274= (c.822G>A) is rare (popmax 0.117%, sas) (gnomAD).

CLN6 p.Ala274=

c.822G>A · rs151186473 · VCV136801

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.117%, sas)

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -4.1
Overall
CADD	2.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.117% South Asian · 107/91,084 alleles

Filtering AF 0.0994% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0927%

Overall 0.053% 856/1,614,060 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.117%	851
European (non-Finnish)	0.0594%	1,683
Remaining individualsnot grpmax-eligible	0.0384%	2,604
African / African-American	0.0253%	3,948
Admixed American	0.005%	20,006
East Asian	0.00223%	44,868
Finnishnot grpmax-eligible	0.00156%	63,954

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.Ala274=
Coding: c.822G>A
MANE Select: NM_017882
dbSNP: rs151186473
Type: single nucleotide variant
Location: chr15:68208254 (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

neuronal ceroid lipofuscinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLN6 p.Ala274Val Uncertain significance ★★ ⚠ 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.84-1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN6 p.Arg103Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
CLN6 p.Arg149Cys 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-ala274 (accessed [today's date]).

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