Is PDE6B p.Pro126Arg (c.377C>G) pathogenic?

PDE6B p.Pro126Arg (c.377C>G) is classified Uncertain significance in PDE6B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-22). AlphaMissense: ambiguous (0.4885); Very rare (popmax 8.57e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PDE6B p.Pro126Arg (c.377C>G)?

PDE6B p.Pro126Arg (c.377C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PDE6B p.Pro126Arg (c.377C>G) in the general population?

PDE6B p.Pro126Arg (c.377C>G) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

What do computational predictors say about PDE6B p.Pro126Arg (c.377C>G)?

AlphaMissense predicts ambiguous (score 0.4885) — an in-silico prediction, not a clinical call.

PDE6B p.Pro126Arg

c.377C>G · rs1253425548 · VCV2004032

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4885 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4885	ambiguous
REVEL	0.576	indeterminate
SaProt	LLR -5.33	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 44 kb · p 0.27 · regional, not allelic
Overall
CADD	25.1	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 8.57e-05% European (non-Finnish) · 1/1,166,472 alleles

Overall 6.98e-05% 1/1,433,242 alleles · very rare

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.Pro126Arg
Coding: c.377C>G
MANE Select: NM_000283
dbSNP: rs1253425548
Type: single nucleotide variant
Location: chr4:626003 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.72
Residue 126: the gaf 1 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.Pro126Ser Uncertain significance ★ ⚠ same residue
PDE6B p.Pro126= Likely benign ★ 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-pro126arg (accessed [today's date]).

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