Is PDE6B p.Arg100Cys (c.298C>T) pathogenic?

PDE6B p.Arg100Cys (c.298C>T) is classified Conflicting classifications of pathogenicity in PDE6B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-13). AlphaMissense: likely pathogenic (0.6226); Rare (popmax 0.201%, sas); Associated with retinitis pigmentosa.

What condition is associated with PDE6B p.Arg100Cys (c.298C>T)?

PDE6B p.Arg100Cys (c.298C>T) is associated with retinitis pigmentosa, congenital stationary night blindness autosomal dominant 2 (ClinVar).

How common is PDE6B p.Arg100Cys (c.298C>T) in the general population?

PDE6B p.Arg100Cys (c.298C>T) is rare (popmax 0.201%, sas) (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.Arg100Cys (c.298C>T)?

AlphaMissense predicts likely pathogenic (score 0.6226) — an in-silico prediction, not a clinical call.

PDE6B p.Arg100Cys

c.298C>T · rs537263212 · VCV903745

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6226 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.201%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.6226	likely pathogenic
REVEL	0.677	pathogenic-leaning
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 44 kb · p 0.27 · regional, not allelic
Overall
CADD	29.1	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 0.201% South Asian · 179/89,264 alleles

Filtering AF 0.176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.167%

Overall 0.0124% 199/1,598,496 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.201%	499
Remaining individualsnot grpmax-eligible	0.0113%	8,845
Finnishnot grpmax-eligible	0.00324%	30,840
European (non-Finnish)	0.000938%	106,638

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.Arg100Cys
Coding: c.298C>T
MANE Select: NM_000283
dbSNP: rs537263212
Type: single nucleotide variant
Location: chr4:625924 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.72
Residue 100: a UniProt-annotated variant site (in rp40); the gaf 1 domain

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

Disease context

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

Also linked: congenital stationary night blindness autosomal dominant 2

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.Arg100His Conflicting classifications of pathogenicity ★ ⚠ same residue
PDE6B p.Arg100Leu Uncertain significance ★ ⚠ same residue
PDE6B c.1060-1G>T Pathogenic/Likely pathogenic ★★ same condition
PDE6B c.1107+3A>G Pathogenic/Likely pathogenic ★★ same condition
PDE6B c.1832+1G>T Pathogenic ★★ same condition
PDE6B c.1921-9C>G Pathogenic ★★ same condition
PDE6B c.2021+2T>G Pathogenic/Likely 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-arg100cys (accessed [today's date]).

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