Is PDE6D p.Arg75His (c.224G>A) pathogenic?

PDE6D p.Arg75His (c.224G>A) is classified Uncertain significance in PDE6D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-07). AlphaMissense: ambiguous (0.3552); Ultra-rare (popmax 0.011%, sas); Associated with Joubert syndrome 22.

What condition is associated with PDE6D p.Arg75His (c.224G>A)?

PDE6D p.Arg75His (c.224G>A) is associated with Joubert syndrome 22 (ClinVar).

How common is PDE6D p.Arg75His (c.224G>A) in the general population?

PDE6D p.Arg75His (c.224G>A) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about PDE6D p.Arg75His (c.224G>A)?

AlphaMissense predicts ambiguous (score 0.3552) — an in-silico prediction, not a clinical call.

PDE6D p.Arg75His

c.224G>A · rs367809264 · VCV2151819

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3552 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Joubert syndrome 22

Computational evidence

Protein change
AlphaMissense	0.3552	ambiguous
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -10.42	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 0.67, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 48 kb · p 0.00076 · regional, not allelic
Overall
CADD	32.0	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 0.011% South Asian · 10/91,054 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00409% 66/1,613,742 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,105
East Asian	0.00445%	22,448
European (non-Finnish)	0.00415%	24,079
African / African-American	0.00401%	24,967
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00167%	59,944

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.Arg75His
Coding: c.224G>A
MANE Select: NM_002601
dbSNP: rs367809264
Type: single nucleotide variant
Location: chr2:231738054 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI 0.23 (gnomAD)
Structure: AlphaFold pLDDT 96.40 · 40 PDB
Residue 75: 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.Arg75Cys Uncertain significance ★ ⚠ same residue
PDE6D p.Arg75= Likely benign ★ same residue
PDE6D p.Arg23Trp 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

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-arg75his (accessed [today's date]).

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