Is CLN6 p.Pro299His (c.896C>A) pathogenic?

CLN6 p.Pro299His (c.896C>A) is classified Likely pathogenic in CLN6 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9913); Absent from gnomAD v4.1; Associated with ceroid lipofuscinosis, neuronal, 6A.

What condition is associated with CLN6 p.Pro299His (c.896C>A)?

CLN6 p.Pro299His (c.896C>A) is associated with ceroid lipofuscinosis, neuronal, 6A (ClinVar).

How common is CLN6 p.Pro299His (c.896C>A) in the general population?

CLN6 p.Pro299His (c.896C>A) is absent from gnomAD v4.1 (gnomAD).

How is CLN6 disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CLN6 p.Pro299His (c.896C>A)?

AlphaMissense predicts likely pathogenic (score 0.9913) — an in-silico prediction, not a clinical call.

CLN6 p.Pro299His

c.896C>A · rs758921701 · VCV1199253

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9913 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ceroid lipofuscinosis, neuronal, 6A

Computational evidence

Protein change
AlphaMissense	0.9913	likely pathogenic ✓ concordant with ClinVar · top 4% in CLN6
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -8.77	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 21 kb · p 0.14 · regional, not allelic
Overall
CADD	29.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLN6
Protein: p.Pro299His
Coding: c.896C>A
MANE Select: NM_017882
dbSNP: rs758921701
Type: single nucleotide variant
Location: chr15:68208180 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.86
Residue 299: 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, 6A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CLN6 disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CLN6 p.Pro299Leu Pathogenic ★★ ⚠ same residue
CLN6 c.486+1G>A Likely pathogenic ★★ same condition
CLN6 c.543-1G>A 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
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-pro299his (accessed [today's date]).

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