Is PDE6B p.Val75fs (c.222dup) pathogenic?

PDE6B p.Val75fs (c.222dup) is classified Pathogenic in PDE6B (ClinVar, Single submitter, 2 submitters; last evaluated 2020-01-09). Very rare (popmax 0.0011%, sas); Associated with cone-rod dystrophy.

What condition is associated with PDE6B p.Val75fs (c.222dup)?

PDE6B p.Val75fs (c.222dup) is associated with cone-rod dystrophy, inherited retinal dystrophy (ClinVar).

How common is PDE6B p.Val75fs (c.222dup) in the general population?

PDE6B p.Val75fs (c.222dup) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Cone rod dystrophy inherited?

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

PDE6B p.Val75fs

c.222dup · rs1734066547 · VCV813067

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

cone-rod dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.2	GERP -2.6, phastCons 0.25

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,986 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,460,146 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,986
European (non-Finnish)	0.00017%	589,838

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.Val75fs
Coding: c.222dup
MANE Select: NM_000283
dbSNP: rs1734066547
Type: Duplication
Location: chr4:625847 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.72
Residue 75: the gaf 1 domain

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

Disease context

cone-rod dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inherited retinal dystrophy

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

PDE6B c.928-9_940dup Benign/Likely benign ★★ same condition
PDE6B p.Lys674fs Likely pathogenic ★ same condition
PDE6B p.Val75Met 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.1468-2A>G Pathogenic/Likely pathogenic ★★ same condition
PDE6B c.1921-9C>G Pathogenic ★★ same condition
PDE6B p.Ala143fs 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-val75fs (accessed [today's date]).

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