Is PDE6A p.Arg66Trp (c.196C>T) pathogenic?

PDE6A p.Arg66Trp (c.196C>T) is classified Uncertain significance in PDE6A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-05). AlphaMissense: likely benign (0.1788); Ultra-rare (popmax 0.0493%, mid); Associated with retinitis pigmentosa.

What condition is associated with PDE6A p.Arg66Trp (c.196C>T)?

PDE6A p.Arg66Trp (c.196C>T) is associated with retinitis pigmentosa, retinitis pigmentosa 43, inherited retinal dystrophy (ClinVar).

How common is PDE6A p.Arg66Trp (c.196C>T) in the general population?

PDE6A p.Arg66Trp (c.196C>T) is ultra-rare (popmax 0.0493%, mid) (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 PDE6A p.Arg66Trp (c.196C>T)?

AlphaMissense predicts likely benign (score 0.1788) — an in-silico prediction, not a clinical call.

PDE6A p.Arg66Trp

c.196C>T · rs149945348 · VCV837054

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1788 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.1788	likely benign
REVEL	0.335	indeterminate
SaProt	LLR -10.72	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 77 kb · p 0.94 · regional, not allelic
Overall
CADD	23.2	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 0.0493% Middle Eastern · 3/6,080 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0237%

Overall 0.0226% 365/1,613,952 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
Admixed American	0.0283%	3,529
European (non-Finnish)	0.0271%	3,688
Remaining individualsnot grpmax-eligible	0.0256%	3,905
African / African-American	0.00534%	18,724
South Asian	0.00439%	22,771
Finnishnot grpmax-eligible	0.00156%	64,012

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: PDE6A
Protein: p.Arg66Trp
Coding: c.196C>T
MANE Select: NM_000440
dbSNP: rs149945348
Type: single nucleotide variant
Location: chr5:149944478 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.80
Residue 66: the gaf 1 domain

Full PDE6A 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: retinitis pigmentosa 43 inherited retinal dystrophy

For Retinitis pigmentosa (Orphanet):

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

Similar variants

PDE6A p.Arg66Gln Uncertain significance ★★ ⚠ same residue
PDE6A c.1065+2T>A Pathogenic/Likely pathogenic ★★ same condition
PDE6A c.1407+1G>C Pathogenic/Likely pathogenic ★★ same condition
PDE6A c.1620+1G>A Pathogenic ★★ same condition
PDE6A c.1620+2T>A Pathogenic/Likely pathogenic ★★ same condition
PDE6A c.1926+1G>A Pathogenic ★★ same condition
PDE6A c.1927-1G>C Pathogenic/Likely pathogenic ★★ same condition
PDE6A c.2027+2T>G Pathogenic/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/pde6a-p-arg66trp (accessed [today's date]).

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