Is PDE6D p.Asp135= (c.405C>T) pathogenic?

PDE6D p.Asp135= (c.405C>T) is classified Likely benign in PDE6D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). Very rare (popmax 0.004%, afr); Associated with Joubert syndrome 22.

What condition is associated with PDE6D p.Asp135= (c.405C>T)?

PDE6D p.Asp135= (c.405C>T) is associated with Joubert syndrome 22 (ClinVar).

How common is PDE6D p.Asp135= (c.405C>T) in the general population?

PDE6D p.Asp135= (c.405C>T) is very rare (popmax 0.004%, afr) (gnomAD).

PDE6D p.Asp135=

c.405C>T · rs373459369 · VCV1577483

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

Joubert syndrome 22

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.32	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.6	GERP -2.2, phastCons 0.99
Overall
CADD	8.477	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,970 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00254% 41/1,611,668 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,990
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592
South Asian	0.0033%	30,332
European (non-Finnish)	0.00289%	34,643

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.Asp135=
Coding: c.405C>T
MANE Select: NM_002601
dbSNP: rs373459369
Type: single nucleotide variant
Location: chr2:231733000 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI 0.23 (gnomAD)
Structure: AlphaFold pLDDT 96.40 · 40 PDB
Residue 135: a β-strand

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-asp135 (accessed [today's date]).

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