Is RBCK1 p.Ser50Phe (c.149C>T) pathogenic?

RBCK1 p.Ser50Phe (c.149C>T) is classified Uncertain significance in RBCK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-05). AlphaMissense: likely benign (0.0757); Very rare (popmax 0.0011%, sas); Associated with polyglucosan body myopathy 1 with or without immunodeficiency.

What condition is associated with RBCK1 p.Ser50Phe (c.149C>T)?

RBCK1 p.Ser50Phe (c.149C>T) is associated with polyglucosan body myopathy 1 with or without immunodeficiency (ClinVar).

How common is RBCK1 p.Ser50Phe (c.149C>T) in the general population?

RBCK1 p.Ser50Phe (c.149C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Polyglucosan body myopathy type 1 inherited?

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

What do computational predictors say about RBCK1 p.Ser50Phe (c.149C>T)?

AlphaMissense predicts likely benign (score 0.0757) — an in-silico prediction, not a clinical call.

RBCK1 p.Ser50Phe

c.149C>T · rs1307466331 · VCV2908896

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0757 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

polyglucosan body myopathy 1 with or without immunodeficiency

Computational evidence

Protein change
AlphaMissense	0.0757	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.93	GERP 0.021, phastCons 0.001
Regional constraint	o/e 0.95	unconstrained · MANE · 12 kb · p 0.36 · regional, not allelic
Overall
CADD	14.5	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 0.0011% South Asian · 1/91,062 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,962 alleles · very rare exomes 4/1,461,694 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,062
European (non-Finnish)	0.000254%	393,301

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: RBCK1
Protein: p.Ser50Phe
Coding: c.149C>T
MANE Select: NM_031229
dbSNP: rs1307466331
Type: single nucleotide variant
Location: chr20:410007 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.34 · 11 PDB
Residue 50: a modified residue (phosphoserine); the 'interaction with tab2' region; the 'interaction with irf3' region

Full RBCK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

polyglucosan body myopathy 1 with or without immunodeficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Polyglucosan body myopathy type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

RBCK1 p.Ser50= Benign/Likely benign ★★ same residue
RBCK1 c.1308+1G>T Pathogenic/Likely pathogenic ★★ same condition
RBCK1 c.582+1G>A Likely pathogenic ★★ same condition
RBCK1 p.Arg352Ter Pathogenic ★★ same condition
RBCK1 p.Gln249Ter Pathogenic/Likely pathogenic ★★ same condition
RBCK1 c.-9C>A Uncertain significance ★★ same condition
RBCK1 p.Ala20Val Uncertain significance ★★ ⚠ same condition
RBCK1 p.Ala228Thr 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/rbck1-p-ser50phe (accessed [today's date]).

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