Is PDE6B p.Arg531Pro (c.1592G>C) pathogenic?

PDE6B p.Arg531Pro (c.1592G>C) is classified Uncertain significance in PDE6B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-26). AlphaMissense: ambiguous (0.4738); Very rare (popmax 0.00347%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PDE6B p.Arg531Pro (c.1592G>C)?

PDE6B p.Arg531Pro (c.1592G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PDE6B p.Arg531Pro (c.1592G>C) in the general population?

PDE6B p.Arg531Pro (c.1592G>C) is very rare (popmax 0.00347%, nfe) (gnomAD).

What do computational predictors say about PDE6B p.Arg531Pro (c.1592G>C)?

AlphaMissense predicts ambiguous (score 0.4738) — an in-silico prediction, not a clinical call.

PDE6B p.Arg531Pro

c.1592G>C · rs144664551 · VCV1051065

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4738	ambiguous
REVEL	0.41	indeterminate
SaProt	LLR -8.07	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -4.2, phastCons 0.012
Regional constraint	o/e 1.03	unconstrained · MANE · 44 kb · p 0.27 · regional, not allelic
Overall
CADD	24.5	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 0.00347% European (non-Finnish) · 41/1,179,968 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.0026% 42/1,613,638 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00347%	28,780
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Arg531Pro
Coding: c.1592G>C
MANE Select: NM_000283
dbSNP: rs144664551
Type: single nucleotide variant
Location: chr4:660591 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.72
Residue 531: the pdease domain

Full PDE6B 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

Similar variants

PDE6B p.Arg531Ter Pathogenic ★★ same residue
PDE6B p.Arg531Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PDE6B p.Ala19Ser Uncertain significance ★★ ⚠ same condition
PDE6B p.Ala341Thr Uncertain significance ★★ ⚠ same condition
PDE6B p.Ala34Thr Uncertain significance ★★ ⚠ same condition
PDE6B p.Ala589Thr Uncertain significance ★★ ⚠ same condition
PDE6B p.Ala809Val Uncertain significance ★★ ⚠ same condition
PDE6B p.Ala845Glu Uncertain significance ★★ ⚠ 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-arg531pro (accessed [today's date]).

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