Is CUBN p.Arg2283= (c.6849G>A) pathogenic?

CUBN p.Arg2283= (c.6849G>A) is classified Conflicting classifications of pathogenicity in CUBN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-11). Very rare (popmax 0.0028%, nfe); Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Arg2283= (c.6849G>A)?

CUBN p.Arg2283= (c.6849G>A) is associated with Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome (ClinVar).

How common is CUBN p.Arg2283= (c.6849G>A) in the general population?

CUBN p.Arg2283= (c.6849G>A) is very rare (popmax 0.0028%, nfe) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

CUBN p.Arg2283=

c.6849G>A · rs373804380 · VCV697864

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Conditions

Imerslund-Grasbeck syndrome type 1

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 -2.9	GERP -2.4
Overall
CADD	1.168	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0028% European (non-Finnish) · 33/1,179,830 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00217% 35/1,613,670 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,752
Admixed American	0.00167%	59,972
African / African-American	0.00134%	74,878

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.Arg2283=
Coding: c.6849G>A
MANE Select: NM_001081
dbSNP: rs373804380
Type: single nucleotide variant
Location: chr10:16918773 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2283: a disulfide bond; a UniProt-annotated variant site (in prochob); the cub 16 domain

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

Disease context

Imerslund-Grasbeck syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Imerslund-Grasbeck syndrome

For Imerslund-Gräsbeck syndrome (Orphanet):

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

Similar variants

CUBN p.Arg2283Trp Uncertain significance ★★ same residue
CUBN p.Arg2283Gln Uncertain significance ★ same residue
CUBN c.10033-1G>A Likely pathogenic ★★ same condition
CUBN c.1230+1G>A Pathogenic/Likely pathogenic ★★ same condition
CUBN c.3672+2T>C Likely pathogenic ★★ same condition
CUBN c.3829+1G>A Pathogenic/Likely pathogenic ★★ same condition
CUBN c.4350+2T>C Likely pathogenic ★★ same condition
CUBN c.6821+3A>G 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-arg2283 (accessed [today's date]).

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