Is PRKAR1A p.Pro334Ser (c.1000C>T) pathogenic?

PRKAR1A p.Pro334Ser (c.1000C>T) is classified Uncertain significance in PRKAR1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely pathogenic (0.8644); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PRKAR1A p.Pro334Ser (c.1000C>T)?

PRKAR1A p.Pro334Ser (c.1000C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PRKAR1A p.Pro334Ser (c.1000C>T) in the general population?

PRKAR1A p.Pro334Ser (c.1000C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRKAR1A p.Pro334Ser (c.1000C>T)?

AlphaMissense predicts likely pathogenic (score 0.8644) — an in-silico prediction, not a clinical call.

PRKAR1A p.Pro334Ser

c.1000C>T · VCV3938087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8644 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8644	likely pathogenic
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -13.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 35 bp · p 1.9e-05 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: PRKAR1A
Protein: p.Pro334Ser
Coding: c.1000C>T
MANE Select: NM_002734
Type: single nucleotide variant
Location: chr17:68530303 (GRCh38)
Gene constraint: LOEUF 0.158 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.95 · 3 PDB

Full PRKAR1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRKAR1A p.Pro334Leu Uncertain significance ★★ ⚠ same residue
PRKAR1A p.Pro334His Uncertain significance ★ ⚠ same residue
PRKAR1A c.502+1G>A Pathogenic/Likely pathogenic ★★ same condition
PRKAR1A c.891+3A>G Likely pathogenic ★★ same condition
PRKAR1A c.892-2A>G Pathogenic/Likely pathogenic ★★ same condition
PRKAR1A p.Arg16Ter Pathogenic ★★ same condition
PRKAR1A p.Arg97Ter Pathogenic ★★ same condition
PRKAR1A p.Met1Val Pathogenic ★★ 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/prkar1a-p-pro334ser (accessed [today's date]).

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