Is PDE1A p.Met396Val (c.1186A>G) pathogenic?

PDE1A p.Met396Val (c.1186A>G) is classified Uncertain significance in PDE1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.0925); Very rare (popmax 0.00167%, amr).

How common is PDE1A p.Met396Val (c.1186A>G) in the general population?

PDE1A p.Met396Val (c.1186A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PDE1A p.Met396Val (c.1186A>G)?

AlphaMissense predicts likely benign (score 0.0925) — an in-silico prediction, not a clinical call.

PDE1A p.Met396Val

c.1186A>G · VCV3929983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0925	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -7.00	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 2.4	GERP 2.9, phastCons 1
Overall
CADD	22.7	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM M412V vs ClinVar M396V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,934 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,612,518 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,934
Remaining individualsnot grpmax-eligible	0.0016%	62,446
European (non-Finnish)	0.00017%	589,418

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: PDE1A
Protein: p.Met396Val
Coding: c.1186A>G
MANE Select: NM_001363871
Type: single nucleotide variant
Location: chr2:182189000 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.12
Residue 396: the pdease domain

Full PDE1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE1A c.1004+24G>T Benign ★★ same type
PDE1A c.101+113C>T Benign ★★ same type
PDE1A c.1207+48G>C Benign ★★ same type
PDE1A c.1207+62A>T Benign ★★ same type
PDE1A c.1208-106T>C Benign ★★ same type
PDE1A c.1516+17841A>G Benign ★★ same type
PDE1A c.168-1739A>C Benign ★★ same type
PDE1A c.168-1806A>G Benign ★★ 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/pde1a-p-met396val (accessed [today's date]).

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