Is PDE1C p.Pro587Ser (c.1759C>T) pathogenic?

PDE1C p.Pro587Ser (c.1759C>T) is classified Uncertain significance in PDE1C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). AlphaMissense: likely benign (0.0681); Very rare (popmax 0.00267%, afr).

How common is PDE1C p.Pro587Ser (c.1759C>T) in the general population?

PDE1C p.Pro587Ser (c.1759C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PDE1C p.Pro587Ser (c.1759C>T)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

PDE1C p.Pro587Ser

c.1759C>T · VCV3305354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -4.03	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 0.015	GERP -2.3, phastCons 0.001
Regional constraint	o/e 0.99	unconstrained · MANE · 85 kb · p 0.8 · regional, not allelic
Overall
CADD	0.631	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 0.00267% African / African-American · 2/74,892 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,613,826 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,446
Admixed American	0.00167%	59,978
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: PDE1C
Protein: p.Pro587Ser
Coding: c.1759C>T
MANE Select: NM_001191057
Type: single nucleotide variant
Location: chr7:31815978 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.53
Residue 587: the 'disordered' region

Full PDE1C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE1C p.Pro587Thr Uncertain significance ★ ⚠ same residue
PDE1C p.Arg45Gln Uncertain significance ★★ ⚠ same type
PDE1C p.His619Tyr Uncertain significance ★★ ⚠ same type
PPP1R17 p.Asp21Glu Uncertain significance ★★ ⚠ same type
PPP1R17 p.Gln8Arg Uncertain significance ★★ ⚠ same type
PDE1C c.1203+28A>G Benign ★★ same type
PDE1C p.Ala594= Benign ★★ same type
PDE1C p.Arg635His Likely 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/pde1c-p-pro587ser (accessed [today's date]).

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