Is PDE6B p.Leu134Pro (c.401T>C) pathogenic?

PDE6B p.Leu134Pro (c.401T>C) is classified Uncertain significance in PDE6B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-24). AlphaMissense: ambiguous (0.4932); Ultra-rare (popmax 0.0136%, eas).

How common is PDE6B p.Leu134Pro (c.401T>C) in the general population?

PDE6B p.Leu134Pro (c.401T>C) is ultra-rare (popmax 0.0136%, eas) (gnomAD).

What do computational predictors say about PDE6B p.Leu134Pro (c.401T>C)?

AlphaMissense predicts ambiguous (score 0.4932) — an in-silico prediction, not a clinical call.

PDE6B p.Leu134Pro

c.401T>C · rs758700964 · VCV1011894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4932 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4932	ambiguous
REVEL	0.737	pathogenic-leaning
SaProt	LLR -10.99	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 44 kb · p 0.27 · regional, not allelic
Overall
CADD	25.5	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 0.0136% East Asian · 6/44,000 alleles

Filtering AF 0.00588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.004%

Overall 0.000416% 6/1,443,184 alleles · ultra-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.Leu134Pro
Coding: c.401T>C
MANE Select: NM_000283
dbSNP: rs758700964
Type: single nucleotide variant
Location: chr4:626027 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.72
Residue 134: the gaf 1 domain

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

Similar variants

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
PDE6B c.1921-1G>A Pathogenic ★★ same type
PDE6B c.1921-2A>G Likely 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-leu134pro (accessed [today's date]).

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