Is PDE6D p.Ser39fs (c.114del) pathogenic?

PDE6D p.Ser39fs (c.114del) is classified Pathogenic in PDE6D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). Very rare (popmax 0.000594%, nfe); Associated with Joubert syndrome 22.

What condition is associated with PDE6D p.Ser39fs (c.114del)?

PDE6D p.Ser39fs (c.114del) is associated with Joubert syndrome 22 (ClinVar).

How common is PDE6D p.Ser39fs (c.114del) in the general population?

PDE6D p.Ser39fs (c.114del) is very rare (popmax 0.000594%, nfe) (gnomAD).

PDE6D p.Ser39fs

c.114del · rs772392692 · VCV1382726

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Conditions

Joubert syndrome 22

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000594% European (non-Finnish) · 7/1,178,704 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000548% 8/1,460,428 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
European (non-Finnish)grpmax	0.000594%	168,386

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PDE6D
Protein: p.Ser39fs
Coding: c.114del
MANE Select: NM_002601
dbSNP: rs772392692
Type: Deletion
Location: chr2:231739125 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI 0.23 (gnomAD)
Structure: AlphaFold pLDDT 96.40 · 40 PDB

Full PDE6D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome 22 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE6D p.Ser39= Likely benign ★ same residue
PDE6D p.Arg23fs Pathogenic ★ same condition
PDE6D p.Cys86fs Likely pathogenic ★ same condition
PDE6D p.Glu114fs Pathogenic ★ same condition
PDE6D c.51-19del Likely benign ★ same condition
PDE6D p.Arg23Trp Uncertain significance ★★ ⚠ same condition
PDE6D p.Arg75His Uncertain significance ★★ ⚠ same condition
PDE6D c.140-3C>T Likely benign ★★ 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/pde6d-p-ser39fs (accessed [today's date]).

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