Is PDE6D p.Arg61Ter (c.181C>T) pathogenic?

PDE6D p.Arg61Ter (c.181C>T) is classified Pathogenic in PDE6D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-23). Very rare (popmax 0.00167%, amr); Associated with Joubert syndrome 22.

What condition is associated with PDE6D p.Arg61Ter (c.181C>T)?

PDE6D p.Arg61Ter (c.181C>T) is associated with Joubert syndrome 22 (ClinVar).

How common is PDE6D p.Arg61Ter (c.181C>T) in the general population?

PDE6D p.Arg61Ter (c.181C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

PDE6D p.Arg61Ter

c.181C>T · rs536550976 · VCV2181645

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Joubert syndrome 22

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 5
Splicing
SpliceAI	Δ0.51	acceptor loss · deltas
Pangolin	Δ0.31	loss · gain 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,982 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,748 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,982
European (non-Finnish)	0.000509%	196,619

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.Arg61Ter
Coding: c.181C>T
MANE Select: NM_002601
dbSNP: rs536550976
Type: single nucleotide variant
Location: chr2:231738097 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI 0.23 (gnomAD)
Structure: AlphaFold pLDDT 96.40 · 40 PDB
Residue 61: 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.Arg61Gln Uncertain significance ★ ⚠ same residue
PDE6D p.Arg61= Likely benign ★ same residue
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

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-arg61ter (accessed [today's date]).

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