Is PDE6D p.Thr35Ala (c.103A>G) pathogenic?

PDE6D p.Thr35Ala (c.103A>G) is classified Uncertain significance in PDE6D (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-13). AlphaMissense: likely benign (0.1613); Very rare (popmax 0.00659%, sas); Associated with Joubert syndrome 22.

What condition is associated with PDE6D p.Thr35Ala (c.103A>G)?

PDE6D p.Thr35Ala (c.103A>G) is associated with Joubert syndrome 22 (ClinVar).

How common is PDE6D p.Thr35Ala (c.103A>G) in the general population?

PDE6D p.Thr35Ala (c.103A>G) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about PDE6D p.Thr35Ala (c.103A>G)?

AlphaMissense predicts likely benign (score 0.1613) — an in-silico prediction, not a clinical call.

PDE6D p.Thr35Ala

c.103A>G · rs1448692172 · VCV1410677

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome 22

Computational evidence

Protein change
AlphaMissense	0.1613	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -10.97	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 1.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 48 kb · p 0.00076 · regional, not allelic
Overall
CADD	22.3	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 0.00659% South Asian · 6/91,066 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000558% 9/1,613,178 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,178
European (non-Finnish)	0.000254%	393,106

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.Thr35Ala
Coding: c.103A>G
MANE Select: NM_002601
dbSNP: rs1448692172
Type: single nucleotide variant
Location: chr2:231739136 (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.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-thr35ala (accessed [today's date]).

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