Is PDE6D p.Arg48His (c.143G>A) pathogenic?

PDE6D p.Arg48His (c.143G>A) is classified Uncertain significance in PDE6D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely benign (0.3201); Very rare (popmax 0.00442%, sas); Associated with Joubert syndrome 22.

What condition is associated with PDE6D p.Arg48His (c.143G>A)?

PDE6D p.Arg48His (c.143G>A) is associated with Joubert syndrome 22 (ClinVar).

How common is PDE6D p.Arg48His (c.143G>A) in the general population?

PDE6D p.Arg48His (c.143G>A) is very rare (popmax 0.00442%, sas) (gnomAD).

What do computational predictors say about PDE6D p.Arg48His (c.143G>A)?

AlphaMissense predicts likely benign (score 0.3201) — an in-silico prediction, not a clinical call.

PDE6D p.Arg48His

c.143G>A · VCV3713605

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00442%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Joubert syndrome 22

Computational evidence

Protein change
AlphaMissense	0.3201	likely benign
REVEL	0.408	indeterminate
SaProt	LLR -6.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 48 kb · p 0.00076 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00442% South Asian · 4/90,556 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000895%

Overall 0.000931% 15/1,610,796 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00442%	22,639
East Asian	0.00223%	44,848
Finnishnot grpmax-eligible	0.00156%	63,992
European (non-Finnish)	0.000763%	130,976

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.Arg48His
Coding: c.143G>A
MANE Select: NM_002601
Type: single nucleotide variant
Location: chr2:231738135 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI 0.23 (gnomAD)
Structure: AlphaFold pLDDT 96.40 · 40 PDB
Residue 48: 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-arg48his (accessed [today's date]).

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