Is CLN6 p.Pro42Ala (c.124C>G) pathogenic?

CLN6 p.Pro42Ala (c.124C>G) is classified Uncertain significance in CLN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). AlphaMissense: likely benign (0.0886); Very rare (popmax 0.000339%, nfe); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN6 p.Pro42Ala (c.124C>G)?

CLN6 p.Pro42Ala (c.124C>G) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN6 p.Pro42Ala (c.124C>G) in the general population?

CLN6 p.Pro42Ala (c.124C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CLN6 p.Pro42Ala (c.124C>G)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

CLN6 p.Pro42Ala

c.124C>G · rs1003606439 · VCV1001439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.64	indeterminate
SaProt	LLR -3.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 21 kb · p 0.14 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,964 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,718 alleles · very rare

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.Pro42Ala
Coding: c.124C>G
MANE Select: NM_017882
dbSNP: rs1003606439
Type: single nucleotide variant
Location: chr15:68218610 (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.Pro42Ser 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-pro42ala (accessed [today's date]).

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