Is CUBN p.Phe2192fs (c.6576del) pathogenic?

CUBN p.Phe2192fs (c.6576del) is classified Pathogenic in CUBN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-12). Very rare (popmax 0.00314%, nfe); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Phe2192fs (c.6576del)?

CUBN p.Phe2192fs (c.6576del) is associated with Imerslund-Grasbeck syndrome (ClinVar).

How common is CUBN p.Phe2192fs (c.6576del) in the general population?

CUBN p.Phe2192fs (c.6576del) is very rare (popmax 0.00314%, nfe) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

CUBN p.Phe2192fs

c.6576del · VCV3719491

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Conditions

Imerslund-Grasbeck syndrome

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 43 of 67
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.7	GERP 0.95, phastCons 1
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00314% European (non-Finnish) · 37/1,179,780 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00248% 40/1,613,762 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,886
African / African-American	0.00267%	37,494
Remaining individualsnot grpmax-eligible	0.0016%	62,494

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: CUBN
Protein: p.Phe2192fs
Coding: c.6576del
MANE Select: NM_001081
Type: Deletion
Location: chr10:16925311 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2192: a UniProt-annotated variant site (in prochob); the cub 15 domain

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

Disease context

Imerslund-Grasbeck syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Imerslund-Gräsbeck syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Finland)

Similar variants

CUBN c.7001-2del Likely pathogenic ★★ same condition
CUBN p.Ala1031_Tyr1032insTer Pathogenic/Likely pathogenic ★★ same condition
CUBN p.Ala2708_Tyr2709insTer Pathogenic/Likely pathogenic ★★ same condition
CUBN p.Arg1487fs Pathogenic/Likely pathogenic ★★ same condition
CUBN p.Asn1658fs Pathogenic/Likely pathogenic ★★ same condition
CUBN p.Glu2310fs Pathogenic/Likely pathogenic ★★ same condition
CUBN p.Thr622fs Pathogenic ★★ same condition
CUBN p.Tyr1350fs Pathogenic/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/cubn-p-phe2192fs (accessed [today's date]).

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