Is PDE6B p.Pro387Ser (c.1159C>T) pathogenic?

PDE6B p.Pro387Ser (c.1159C>T) is classified Uncertain significance in PDE6B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-08). AlphaMissense: likely pathogenic (0.963); Very rare (popmax 8.48e-05%, nfe).

How common is PDE6B p.Pro387Ser (c.1159C>T) in the general population?

PDE6B p.Pro387Ser (c.1159C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PDE6B p.Pro387Ser (c.1159C>T)?

AlphaMissense predicts likely pathogenic (score 0.963) — an in-silico prediction, not a clinical call.

PDE6B p.Pro387Ser

c.1159C>T · rs2474211399 · VCV2127735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.963	likely pathogenic
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -11.13	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 7.5	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 44 kb · p 0.27 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,652 alleles

Overall 6.2e-05% 1/1,612,770 alleles · very rare exomes 1/1,460,436 · genomes 0/152,334 · joint denominator

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.Pro387Ser
Coding: c.1159C>T
MANE Select: NM_000283
dbSNP: rs2474211399
Type: single nucleotide variant
Location: chr4:656925 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.72
Residue 387: the gaf 2 domain

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

Similar variants

PDE6B p.Pro387Leu Pathogenic ★ same residue
PDE6B p.Pro387= Likely benign ★ same residue
PDE6B c.1059+2T>G Likely pathogenic ★★ same type
PDE6B c.1060-1G>T Pathogenic/Likely pathogenic ★★ same type
PDE6B c.1107+1G>T Likely pathogenic ★★ same type
PDE6B c.1107+3A>G Pathogenic/Likely pathogenic ★★ same type
PDE6B c.1468-2A>G Pathogenic/Likely pathogenic ★★ same type
PDE6B c.1832+1G>T Pathogenic ★★ same type

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-pro387ser (accessed [today's date]).

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