Is PDE12 p.Lys94Arg (c.281A>G) pathogenic?

PDE12 p.Lys94Arg (c.281A>G) is classified Uncertain significance in PDE12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-23). AlphaMissense: likely benign (0.12); Very rare (popmax 0.00214%, nfe).

How common is PDE12 p.Lys94Arg (c.281A>G) in the general population?

PDE12 p.Lys94Arg (c.281A>G) is very rare (popmax 0.00214%, nfe) (gnomAD).

What do computational predictors say about PDE12 p.Lys94Arg (c.281A>G)?

AlphaMissense predicts likely benign (score 0.12) — an in-silico prediction, not a clinical call.

PDE12 p.Lys94Arg

c.281A>G · rs764161345 · VCV2480256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.12 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00214%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.12	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.55, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 3,303 bp · p 0.0013 · regional, not allelic
Overall
CADD	19.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00214% European (non-Finnish) · 25/1,169,678 alleles

Filtering AF 0.00147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00124%

Overall 0.00163% 26/1,599,196 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00214%	46,787
Remaining individualsnot grpmax-eligible	0.00162%	61,676

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: PDE12
Protein: p.Lys94Arg
Coding: c.281A>G
MANE Select: NM_177966
dbSNP: rs764161345
Type: single nucleotide variant
Location: chr3:57556660 (GRCh38)
Gene constraint: LOEUF 0.757 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.45 · 3 PDB
Residue 94: the 'disordered' region

Full PDE12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE12 p.Ala201Thr Uncertain significance ★ ⚠ same type
PDE12 p.Ala206Val Uncertain significance ★ ⚠ same type
PDE12 p.Ala322Pro Uncertain significance ★ ⚠ same type
PDE12 p.Ala404Val Uncertain significance ★ ⚠ same type
PDE12 p.Ala424Thr Uncertain significance ★ ⚠ same type
PDE12 p.Ala79Thr Uncertain significance ★ ⚠ same type
PDE12 p.Arg128Gly Uncertain significance ★ ⚠ same type
PDE12 p.Arg196Cys Uncertain significance ★ ⚠ 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/pde12-p-lys94arg (accessed [today's date]).

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