Is PDE12 p.Met63Val (c.187A>G) pathogenic?

PDE12 p.Met63Val (c.187A>G) is classified Uncertain significance in PDE12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: ambiguous (0.4951); Very rare (popmax 0.00223%, eas).

How common is PDE12 p.Met63Val (c.187A>G) in the general population?

PDE12 p.Met63Val (c.187A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PDE12 p.Met63Val (c.187A>G)?

AlphaMissense predicts ambiguous (score 0.4951) — an in-silico prediction, not a clinical call.

PDE12 p.Met63Val

c.187A>G · rs781626583 · VCV2551357

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4951	ambiguous
REVEL	0.218	benign-leaning
SaProt	LLR -6.46	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 3,303 bp · p 0.0013 · regional, not allelic
Overall
CADD	20.0	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 0.00223% East Asian · 1/44,894 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00161% 26/1,613,370 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
European (non-Finnish)	0.00203%	49,167
Remaining individualsnot grpmax-eligible	0.0016%	62,474

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.Met63Val
Coding: c.187A>G
MANE Select: NM_177966
dbSNP: rs781626583
Type: single nucleotide variant
Location: chr3:57556566 (GRCh38)
Gene constraint: LOEUF 0.757 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.45 · 3 PDB

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-met63val (accessed [today's date]).

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