Is PRKAR1A p.Val221= (c.663G>T) pathogenic?

PRKAR1A p.Val221= (c.663G>T) is classified Likely benign in PRKAR1A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-05). Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with PRKAR1A p.Val221= (c.663G>T)?

PRKAR1A p.Val221= (c.663G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PRKAR1A p.Val221= (c.663G>T) in the general population?

PRKAR1A p.Val221= (c.663G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

PRKAR1A p.Val221=

c.663G>T · rs2143323585 · VCV1754637

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Overall
CADD	11.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,962 alleles

Overall 0.000124% 2/1,613,890 alleles · very rare exomes 2/1,461,760 · genomes 0/152,130 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,962
European (non-Finnish)	8.48e-05%	1,179,928

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.Val221=
Coding: c.663G>T
MANE Select: NM_002734
dbSNP: rs2143323585
Type: single nucleotide variant
Location: chr17:68525867 (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 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
PRKAR1A c.502+4A>G 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/prkar1a-p-val221 (accessed [today's date]).

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