Is PRKAR1B p.Ser258Phe (c.773C>T) pathogenic?

PRKAR1B p.Ser258Phe (c.773C>T) is classified Uncertain significance in PRKAR1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-25). AlphaMissense: likely pathogenic (0.866); Very rare (popmax 0.00223%, eas); Associated with Marbach-Schaaf neurodevelopmental syndrome.

What condition is associated with PRKAR1B p.Ser258Phe (c.773C>T)?

PRKAR1B p.Ser258Phe (c.773C>T) is associated with Marbach-Schaaf neurodevelopmental syndrome (ClinVar).

How common is PRKAR1B p.Ser258Phe (c.773C>T) in the general population?

PRKAR1B p.Ser258Phe (c.773C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Marbach-Schaaf neurodevelopmental syndrome inherited?

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

What do computational predictors say about PRKAR1B p.Ser258Phe (c.773C>T)?

AlphaMissense predicts likely pathogenic (score 0.866) — an in-silico prediction, not a clinical call.

PRKAR1B p.Ser258Phe

c.773C>T · VCV3370300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Marbach-Schaaf neurodevelopmental syndrome

Computational evidence

Protein change
AlphaMissense	0.866	likely pathogenic
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -12.17	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 11	GERP 2, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 17 kb · p 0.00022 · regional, not allelic
Overall
CADD	27.0	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 0.00223% East Asian · 1/44,888 alleles

Overall 0.000124% 2/1,613,504 alleles · very rare exomes 1/1,461,260 · genomes 1/152,244 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
European (non-Finnish)	8.47e-05%	1,180,052

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: PRKAR1B
Protein: p.Ser258Phe
Coding: c.773C>T
MANE Select: NM_001164760
Type: single nucleotide variant
Location: chr7:579374 (GRCh38)
Gene constraint: LOEUF 0.686 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.24 · 3 PDB

Full PRKAR1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Marbach-Schaaf neurodevelopmental syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Marbach-Schaaf neurodevelopmental syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

PRKAR1B p.Arg335Trp Pathogenic/Likely pathogenic ★★ same condition
PRKAR1B p.Arg305Cys Uncertain significance ★★ ⚠ same condition
PRKAR1B p.Arg306Gln Pathogenic ★ ⚠ same condition
PRKAR1B p.Trp190Ter Likely pathogenic ★ same condition
PRKAR1B p.Ala270Val Uncertain significance ★ ⚠ same condition
PRKAR1B p.Ala336Val Uncertain significance ★ ⚠ same condition
PRKAR1B p.Arg357Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
PRKAR1B p.Glu196Lys Conflicting classifications of pathogenicity ★ ⚠ 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/prkar1b-p-ser258phe (accessed [today's date]).

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