Is PRKAR1A p.Phe276Ser (c.827T>C) pathogenic?

PRKAR1A p.Phe276Ser (c.827T>C) is classified Uncertain significance in PRKAR1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.9254); Very rare (popmax 8.48e-05%, nfe); Associated with Carney complex, type 1.

What condition is associated with PRKAR1A p.Phe276Ser (c.827T>C)?

PRKAR1A p.Phe276Ser (c.827T>C) is associated with Carney complex, type 1, hereditary neoplastic syndrome (ClinVar).

How common is PRKAR1A p.Phe276Ser (c.827T>C) in the general population?

PRKAR1A p.Phe276Ser (c.827T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Carney complex inherited?

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

What do computational predictors say about PRKAR1A p.Phe276Ser (c.827T>C)?

AlphaMissense predicts likely pathogenic (score 0.9254) — an in-silico prediction, not a clinical call.

PRKAR1A p.Phe276Ser

c.827T>C · rs2085878339 · VCV938335

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9254 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Carney complex, type 1

Computational evidence

Protein change
AlphaMissense	0.9254	likely pathogenic
REVEL	0.976	strongly pathogenic-leaning
SaProt	LLR -13.35	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 4.3	GERP 2.2, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 7,428 bp · p 4.1e-27 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,914 alleles

Overall 6.2e-05% 1/1,614,026 alleles · very rare exomes 1/1,461,704 · genomes 0/152,322 · 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.Phe276Ser
Coding: c.827T>C
MANE Select: NM_002734
dbSNP: rs2085878339
Type: single nucleotide variant
Location: chr17:68528927 (GRCh38)
Gene constraint: LOEUF 0.158 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.95 · 3 PDB
Residue 276: a β-strand

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

Disease context

Carney complex, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Carney complex (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

PRKAR1A p.Phe276Cys Uncertain significance ★ ⚠ same residue
PRKAR1A p.Phe276Leu Uncertain significance ★ ⚠ same residue
PRKAR1A c.502+1G>A Pathogenic/Likely pathogenic ★★ same condition
PRKAR1A c.549+1G>A Pathogenic/Likely pathogenic ★★ same condition
PRKAR1A c.891+1G>A 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

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-phe276ser (accessed [today's date]).

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