Is PDE6D p.Ser121= (c.363C>T) pathogenic?

PDE6D p.Ser121= (c.363C>T) is classified Likely benign in PDE6D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). Very rare (popmax 0.00551%, sas); Associated with Joubert syndrome 22.

What condition is associated with PDE6D p.Ser121= (c.363C>T)?

PDE6D p.Ser121= (c.363C>T) is associated with Joubert syndrome 22 (ClinVar).

How common is PDE6D p.Ser121= (c.363C>T) in the general population?

PDE6D p.Ser121= (c.363C>T) is very rare (popmax 0.00551%, sas) (gnomAD).

PDE6D p.Ser121=

c.363C>T · rs1206823310 · VCV1625889

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00551%, sas)

Conditions

Joubert syndrome 22

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.12	GERP -0.75, phastCons 0.71
Overall
CADD	9.606	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00551% South Asian · 5/90,670 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.000564% 9/1,594,978 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00551%	18,134
Remaining individualsnot grpmax-eligible	0.00162%	61,836
European (non-Finnish)	0.000258%	387,603

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.Ser121=
Coding: c.363C>T
MANE Select: NM_002601
dbSNP: rs1206823310
Type: single nucleotide variant
Location: chr2:231737195 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI 0.23 (gnomAD)
Structure: AlphaFold pLDDT 96.40 · 40 PDB
Residue 121: an α-helix

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.Arg23Trp Uncertain significance ★★ ⚠ same condition
PDE6D p.Arg75His Uncertain significance ★★ ⚠ same condition
PDE6D c.140-3C>T Likely benign ★★ same condition
PDE6D c.371+8A>C Benign/Likely benign ★★ same condition
PDE6D c.50+11G>C Likely benign ★★ same condition
PDE6D p.Ala58= Likely benign ★★ same condition
PDE6D p.Arg13= Likely benign ★★ same condition
PDE6D p.Asp136Asn 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-ser121 (accessed [today's date]).

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