Is CUBN p.Pro1691= (c.5073C>G) pathogenic?

CUBN p.Pro1691= (c.5073C>G) is classified Conflicting classifications of pathogenicity in CUBN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-26). Ultra-rare (popmax 0.067%, mid); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Pro1691= (c.5073C>G)?

CUBN p.Pro1691= (c.5073C>G) is associated with Imerslund-Grasbeck syndrome, Imerslund-Grasbeck syndrome type 1 (ClinVar).

How common is CUBN p.Pro1691= (c.5073C>G) in the general population?

CUBN p.Pro1691= (c.5073C>G) is ultra-rare (popmax 0.067%, mid) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

CUBN p.Pro1691=

c.5073C>G · rs200977290 · VCV299473

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.067%, mid)

Conditions

Imerslund-Grasbeck syndrome

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 0.65	GERP -1.9, phastCons 0.98
Overall
CADD	1.653	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.067% Middle Eastern · 4/5,972 alleles

Filtering AF 0.0229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00998% 161/1,612,650 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.067%	1,493
Remaining individualsnot grpmax-eligible	0.0208%	4,804
Admixed American	0.0133%	7,499
European (non-Finnish)	0.0115%	8,733
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,578

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.Pro1691=
Coding: c.5073C>G
MANE Select: NM_001081
dbSNP: rs200977290
Type: single nucleotide variant
Location: chr10:16950008 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1691: a disulfide bond; a UniProt-annotated variant site (in prochob); the cub 11 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

Also linked: Imerslund-Grasbeck syndrome type 1

For Imerslund-Gräsbeck syndrome (Orphanet):

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

Similar variants

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
CUBN c.6822-1G>A Likely pathogenic ★★ same condition
CUBN c.8598+1G>T 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-pro1691 (accessed [today's date]).

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