Is PDE6B p.Arg552Trp (c.1654C>T) pathogenic?

PDE6B p.Arg552Trp (c.1654C>T) is classified Pathogenic/Likely pathogenic in PDE6B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-05). AlphaMissense: likely pathogenic (0.9899); Very rare (popmax 0.00346%, sas); Associated with PDE6B-related disorder.

What condition is associated with PDE6B p.Arg552Trp (c.1654C>T)?

PDE6B p.Arg552Trp (c.1654C>T) is associated with PDE6B-related disorder, inherited retinal dystrophy (ClinVar).

How common is PDE6B p.Arg552Trp (c.1654C>T) in the general population?

PDE6B p.Arg552Trp (c.1654C>T) is very rare (popmax 0.00346%, sas) (gnomAD).

What do computational predictors say about PDE6B p.Arg552Trp (c.1654C>T)?

AlphaMissense predicts likely pathogenic (score 0.9899) — an in-silico prediction, not a clinical call.

PDE6B p.Arg552Trp

c.1654C>T · rs1201231261 · VCV1466663

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9899 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00346%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PDE6B-related disorder

Computational evidence

Protein change
AlphaMissense	0.9899	likely pathogenic ✓ concordant with ClinVar · top 8% in PDE6B
REVEL	0.715	pathogenic-leaning
SaProt	LLR -15.34	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 1	GERP -2.5, phastCons 0.84
Regional constraint	o/e 1.03	unconstrained · MANE · 44 kb · p 0.27 · regional, not allelic
Overall
CADD	27.7	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 0.00346% South Asian · 3/86,622 alleles

Filtering AF 0.00092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000455%

Overall 0.000633% 10/1,578,872 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00346%	28,874
African / African-American	0.00135%	74,144
European (non-Finnish)	0.000516%	193,735

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.Arg552Trp
Coding: c.1654C>T
MANE Select: NM_000283
dbSNP: rs1201231261
Type: single nucleotide variant
Location: chr4:662173 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.72
Residue 552: a UniProt-annotated variant site (in rp40; autosomal recessive); the pdease domain

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

Disease context

PDE6B-related disorder

Also linked: inherited retinal dystrophy

Similar variants

PDE6B p.Arg552Gln Pathogenic/Likely pathogenic ★★ 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.1468-2A>G Pathogenic/Likely pathogenic ★★ same condition
PDE6B c.1921-1G>A Pathogenic ★★ same condition
PDE6B c.1921-2A>G Likely 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-arg552trp (accessed [today's date]).

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