Is PDE6B p.His561Arg (c.1682A>G) pathogenic?

PDE6B p.His561Arg (c.1682A>G) is classified Conflicting classifications of pathogenicity in PDE6B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-08). AlphaMissense: likely pathogenic (0.9987); Very rare (popmax 0.00548%, amr); Associated with retinitis pigmentosa 40.

What condition is associated with PDE6B p.His561Arg (c.1682A>G)?

PDE6B p.His561Arg (c.1682A>G) is associated with retinitis pigmentosa 40 (ClinVar).

How common is PDE6B p.His561Arg (c.1682A>G) in the general population?

PDE6B p.His561Arg (c.1682A>G) is very rare (popmax 0.00548%, amr) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PDE6B p.His561Arg (c.1682A>G)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

PDE6B p.His561Arg

c.1682A>G · rs1305333312 · VCV1172721

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00548%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa 40

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 2% in PDE6B
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -13.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 44 kb · p 0.27 · regional, not allelic
Overall
CADD	25.7	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 0.00548% Admixed American · 3/54,728 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000703%

Overall 0.00019% 3/1,578,466 alleles · very rare

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: PDE6B
Protein: p.His561Arg
Coding: c.1682A>G
MANE Select: NM_000283
dbSNP: rs1305333312
Type: single nucleotide variant
Location: chr4:662201 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.72
Residue 561: a binding site; the pdease domain

Full PDE6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa 40 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

PDE6B p.His561Gln Uncertain significance ★ ⚠ same residue
PDE6B p.His561Tyr Uncertain significance ★ ⚠ same residue
PDE6B c.1059+2T>G Likely pathogenic ★★ same condition
PDE6B c.1060-1G>T Pathogenic/Likely pathogenic ★★ same condition
PDE6B c.1107+1G>T Likely pathogenic ★★ same condition
PDE6B c.1107+3A>G Pathogenic/Likely pathogenic ★★ same condition
PDE6B c.1832+1G>T Pathogenic ★★ same condition
PDE6B c.2193+1G>A Pathogenic ★★ 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/pde6b-p-his561arg (accessed [today's date]).

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