Is CLN6 p.Phe236Ser (c.707T>C) pathogenic?

CLN6 p.Phe236Ser (c.707T>C) is classified Uncertain significance in CLN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-22). AlphaMissense: likely pathogenic (0.7628); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CLN6 p.Phe236Ser (c.707T>C)?

CLN6 p.Phe236Ser (c.707T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CLN6 p.Phe236Ser (c.707T>C) in the general population?

CLN6 p.Phe236Ser (c.707T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CLN6 p.Phe236Ser (c.707T>C)?

AlphaMissense predicts likely pathogenic (score 0.7628) — an in-silico prediction, not a clinical call.

CLN6 p.Phe236Ser

c.707T>C · rs2505401809 · VCV1757040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7628	likely pathogenic
REVEL	0.912	moderately pathogenic-leaning
SaProt	LLR -6.54	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 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 21 kb · p 0.14 · regional, not allelic
Overall
CADD	27.4	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 0.000339% European (non-Finnish) · 4/1,180,024 alleles

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

Overall 0.000274% 4/1,461,490 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.Phe236Ser
Coding: c.707T>C
MANE Select: NM_017882
dbSNP: rs2505401809
Type: single nucleotide variant
Location: chr15:68208369 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLN6 p.Phe236Val Uncertain significance ★★ ⚠ same residue
CLN6 c.297+4C>T Uncertain significance ★★ same condition
CLN6 p.Ala240Thr Uncertain significance ★★ ⚠ same condition
CLN6 p.Arg252Cys Uncertain significance ★★ ⚠ same condition
CLN6 p.Gln19His Uncertain significance ★★ ⚠ same condition
CLN6 p.Gly15Cys Uncertain significance ★★ ⚠ same condition
CLN6 p.Ile183Val Uncertain significance ★★ ⚠ same condition
CLN6 p.Ile235Asn Uncertain significance ★★ ⚠ 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-phe236ser (accessed [today's date]).

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