Is PDE6D p.Ala58= (c.174A>G) pathogenic?

PDE6D p.Ala58= (c.174A>G) is classified Likely benign in PDE6D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-19). Ultra-rare (popmax 0.0125%, nfe); Associated with Joubert syndrome 22.

What condition is associated with PDE6D p.Ala58= (c.174A>G)?

PDE6D p.Ala58= (c.174A>G) is associated with Joubert syndrome 22 (ClinVar).

How common is PDE6D p.Ala58= (c.174A>G) in the general population?

PDE6D p.Ala58= (c.174A>G) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

PDE6D p.Ala58=

c.174A>G · rs139835658 · VCV1628271

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

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
Constraint at this position
Conservation	phyloP -1.9	GERP -3.4
Overall
CADD	5.412	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0125% European (non-Finnish) · 147/1,179,664 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00998% 161/1,613,418 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	8,025
Remaining individualsnot grpmax-eligible	0.0096%	10,413
South Asian	0.0077%	12,988
Finnishnot grpmax-eligible	0.00156%	64,042

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.Ala58=
Coding: c.174A>G
MANE Select: NM_002601
dbSNP: rs139835658
Type: single nucleotide variant
Location: chr2:231738104 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI 0.23 (gnomAD)
Structure: AlphaFold pLDDT 96.40 · 40 PDB
Residue 58: 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.Arg13= Likely benign ★★ same condition
PDE6D p.Asp136Asn Likely benign ★★ same condition
PDE6D p.Asp137Asn Benign/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-ala58 (accessed [today's date]).

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