Is PRKAR1A p.Ser3Pro (c.7T>C) pathogenic?

PRKAR1A p.Ser3Pro (c.7T>C) is classified Uncertain significance in PRKAR1A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-18). AlphaMissense: likely benign (0.081); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PRKAR1A p.Ser3Pro (c.7T>C)?

PRKAR1A p.Ser3Pro (c.7T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PRKAR1A p.Ser3Pro (c.7T>C) in the general population?

PRKAR1A p.Ser3Pro (c.7T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PRKAR1A p.Ser3Pro (c.7T>C)?

AlphaMissense predicts likely benign (score 0.081) — an in-silico prediction, not a clinical call.

PRKAR1A p.Ser3Pro

c.7T>C · rs1488444958 · VCV3222775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.081 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.081	likely benign
REVEL	0.426	indeterminate
SaProt	LLR -6.36	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.66	GERP -0.8, phastCons 0.31
Regional constraint	o/e 0.93	unconstrained · MANE · 7,453 bp · p 0.48 · regional, not allelic
Overall
CADD	20.8	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 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,613,030 alleles · very rare exomes 0/1,460,908 · genomes 1/152,122 · joint denominator

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: PRKAR1A
Protein: p.Ser3Pro
Coding: c.7T>C
MANE Select: NM_002734
dbSNP: rs1488444958
Type: single nucleotide variant
Location: chr17:68515406 (GRCh38)
Gene constraint: LOEUF 0.158 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.95 · 3 PDB
Residue 3: the 'dimerization and phosphorylation' region; a modified residue (phosphoserine)

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.Ser3Phe 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
PRKAR1A p.Trp190Ter Pathogenic/Likely 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-ser3pro (accessed [today's date]).

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