Is PRKG1 p.Pro136Ser (c.406C>T) pathogenic?

PRKG1 p.Pro136Ser (c.406C>T) is classified Uncertain significance in PRKG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-18). AlphaMissense: ambiguous (0.3528); Absent from gnomAD v4.1; Associated with aortic aneurysm, familial thoracic 8.

What condition is associated with PRKG1 p.Pro136Ser (c.406C>T)?

PRKG1 p.Pro136Ser (c.406C>T) is associated with aortic aneurysm, familial thoracic 8 (ClinVar).

How common is PRKG1 p.Pro136Ser (c.406C>T) in the general population?

PRKG1 p.Pro136Ser (c.406C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRKG1 p.Pro136Ser (c.406C>T)?

AlphaMissense predicts ambiguous (score 0.3528) — an in-silico prediction, not a clinical call.

PRKG1 p.Pro136Ser

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.406C>T · rs2538641753 · VCV2173700

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3528 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

aortic aneurysm, familial thoracic 8

Computational evidence

Protein change
AlphaMissense	0.3528	ambiguous
REVEL	0.649	pathogenic-leaning
SaProt	LLR -9.11	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 1,206 kb · p 7e-12 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P121S vs ClinVar P136S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PRKG1
Protein: p.Pro136Ser
Coding: c.406C>T
MANE Select: NM_006258
dbSNP: rs2538641753
Type: single nucleotide variant
Location: chr10:51153258 (GRCh38)
Gene constraint: LOEUF 0.534 · pLI 0.66 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 26 PDB
Residue 121 UniProt numbering: a β-strand; the 'cgmp-binding, high affinity' region

Full PRKG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

aortic aneurysm, familial thoracic 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

PRKG1 p.Pro136Leu Uncertain significance ★★ ⚠ same residue
PRKG1 p.Pro136= Benign ★★ same residue
PRKG1 p.Arg192Gln Pathogenic ★★ same condition
PRKG1 c.1001+3A>G Uncertain significance ★★ same condition
PRKG1 c.1832+5G>A Uncertain significance ★★ same condition
PRKG1 c.478+4C>T Uncertain significance ★★ same condition
PRKG1 c.478+5G>A Uncertain significance ★★ same condition
PRKG1 c.840+5G>T Uncertain significance ★★ same condition

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/prkg1-p-pro136ser (accessed [today's date]).

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