Is CLN6 p.Ser104Pro (c.310T>C) pathogenic?

CLN6 p.Ser104Pro (c.310T>C) is classified Uncertain significance in CLN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-02). AlphaMissense: likely pathogenic (0.893); Absent from gnomAD v4.1.

How common is CLN6 p.Ser104Pro (c.310T>C) in the general population?

CLN6 p.Ser104Pro (c.310T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLN6 p.Ser104Pro (c.310T>C)?

AlphaMissense predicts likely pathogenic (score 0.893) — an in-silico prediction, not a clinical call.

CLN6 p.Ser104Pro

c.310T>C · rs1595818378 · VCV2688794

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.893 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.893	likely pathogenic
REVEL	0.873	moderately pathogenic-leaning
SaProt	LLR -12.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 21 kb · p 0.14 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Ser104Pro
Coding: c.310T>C
MANE Select: NM_017882
dbSNP: rs1595818378
Type: single nucleotide variant
Location: chr15:68211851 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.86
Residue 104: a UniProt-annotated variant site (in cln6)

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

Similar variants

CLN6 p.Ser104Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
CLN6 p.Ser104Tyr Uncertain significance ★ ⚠ same residue
CLN6 c.297+1G>A Pathogenic/Likely pathogenic ★★ same type
CLN6 c.486+1G>A Likely pathogenic ★★ same type
CLN6 c.543-1G>A Likely pathogenic ★★ same type
CLN6 c.665+1G>A Pathogenic/Likely pathogenic ★★ same type
CLN6 c.665+1G>T Likely pathogenic ★★ same type
CLN6 c.83+1G>C Likely pathogenic ★★ same type

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-ser104pro (accessed [today's date]).

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