Is PDE6D p.Arg23Trp (c.67C>T) pathogenic?

PDE6D p.Arg23Trp (c.67C>T) is classified Uncertain significance in PDE6D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-13). AlphaMissense: likely pathogenic (0.9887); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with PDE6D p.Arg23Trp (c.67C>T)?

PDE6D p.Arg23Trp (c.67C>T) is associated with Inborn genetic diseases, Joubert syndrome 22 (ClinVar).

How common is PDE6D p.Arg23Trp (c.67C>T) in the general population?

PDE6D p.Arg23Trp (c.67C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PDE6D p.Arg23Trp (c.67C>T)?

AlphaMissense predicts likely pathogenic (score 0.9887) — an in-silico prediction, not a clinical call.

PDE6D p.Arg23Trp

c.67C>T · rs570163390 · VCV1441438

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9887	likely pathogenic
REVEL	0.615	indeterminate
SaProt	LLR -18.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.22	acceptor loss, 30 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 48 kb · p 0.00076 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,020 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,458,482 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,020
European (non-Finnish)	0.000255%	392,323

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.Arg23Trp
Coding: c.67C>T
MANE Select: NM_002601
dbSNP: rs570163390
Type: single nucleotide variant
Location: chr2:231739172 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI 0.23 (gnomAD)
Structure: AlphaFold pLDDT 96.40 · 40 PDB
Residue 23: a β-strand

Full PDE6D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome 22

Similar variants

PDE6D p.Arg23Gln Uncertain significance ★ ⚠ same residue
PDE6D p.Arg23= Likely benign ★ same residue
PDE6D p.Arg23fs Pathogenic ★ same residue
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

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-arg23trp (accessed [today's date]).

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