Is PDE6D p.Thr142Ala (c.424A>G) pathogenic?

PDE6D p.Thr142Ala (c.424A>G) is classified Uncertain significance in PDE6D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-05). AlphaMissense: likely benign (0.1517); Very rare (popmax 8.48e-05%, nfe); Associated with Joubert syndrome 22.

What condition is associated with PDE6D p.Thr142Ala (c.424A>G)?

PDE6D p.Thr142Ala (c.424A>G) is associated with Joubert syndrome 22 (ClinVar).

How common is PDE6D p.Thr142Ala (c.424A>G) in the general population?

PDE6D p.Thr142Ala (c.424A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PDE6D p.Thr142Ala (c.424A>G)?

AlphaMissense predicts likely benign (score 0.1517) — an in-silico prediction, not a clinical call.

PDE6D p.Thr142Ala

c.424A>G · rs1192555580 · VCV2159721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1517 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome 22

Computational evidence

Protein change
AlphaMissense	0.1517	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -11.24	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 48 kb · p 0.00076 · regional, not allelic
Overall
CADD	24.0	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 8.48e-05% European (non-Finnish) · 1/1,178,588 alleles

Overall 6.85e-05% 1/1,460,212 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: PDE6D
Protein: p.Thr142Ala
Coding: c.424A>G
MANE Select: NM_002601
dbSNP: rs1192555580
Type: single nucleotide variant
Location: chr2:231732981 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI 0.23 (gnomAD)
Structure: AlphaFold pLDDT 96.40 · 40 PDB
Residue 142: 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-thr142ala (accessed [today's date]).

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