Is RBCK1 p.Glu299fs (c.896_899del) pathogenic?

RBCK1 p.Glu299fs (c.896899del) is classified Pathogenic in RBCK1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-08). Very rare (popmax 0.00351%, sas); Associated with RBCK1-related disorder.

What condition is associated with RBCK1 p.Glu299fs (c.896_899del)?

RBCK1 p.Glu299fs (c.896_899del) is associated with RBCK1-related disorder, polyglucosan body myopathy 1 with or without immunodeficiency (ClinVar).

How common is RBCK1 p.Glu299fs (c.896_899del) in the general population?

RBCK1 p.Glu299fs (c.896_899del) is very rare (popmax 0.00351%, sas) (gnomAD).

RBCK1 p.Glu299fs

c.896_899del · rs727503764 · VCV140625

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00351%, sas)

Conditions

RBCK1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.5	GERP 2.4, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00351% South Asian · 3/85,456 alleles

Filtering AF 0.000932% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000617%

Overall 0.00134% 21/1,566,960 alleles · very rare exomes 21/1,415,042 · genomes 0/151,918 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00351%	28,485
Ashkenazi Jewishnot grpmax-eligible	0.00348%	28,738
Admixed American	0.00184%	54,382
Remaining individualsnot grpmax-eligible	0.00165%	60,634
European (non-Finnish)	0.0013%	77,132

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.Glu299fs
Coding: c.896_899del
MANE Select: NM_031229
dbSNP: rs727503764
Type: Deletion
Location: chr20:421007 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.34 · 11 PDB
Residue 299: the 'triad supradomain' region; a turn

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

Disease context

RBCK1-related disorder

Also linked: polyglucosan body myopathy 1 with or without immunodeficiency

Similar variants

RBCK1 p.Ala228fs Likely pathogenic ★ same condition
RBCK1 p.Cys202fs Likely pathogenic ★ same condition
RBCK1 p.Glu222fs Pathogenic ★ same condition
RBCK1 p.Gly196fs Pathogenic ★ same condition
RBCK1 p.Gly242fs Likely pathogenic ★ same condition
RBCK1 p.Ile313fs Pathogenic ★ same condition
RBCK1 p.Leu13fs Likely pathogenic ★ same condition
RBCK1 p.Leu301fs 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/rbck1-p-glu299fs (accessed [today's date]).

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