Is CUBN p.Pro1297= (c.3891G>A) pathogenic?

CUBN p.Pro1297= (c.3891G>A) is classified Likely benign in CUBN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). Very rare (popmax 0.0017%, nfe); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Pro1297= (c.3891G>A)?

CUBN p.Pro1297= (c.3891G>A) is associated with Imerslund-Grasbeck syndrome (ClinVar).

How common is CUBN p.Pro1297= (c.3891G>A) in the general population?

CUBN p.Pro1297= (c.3891G>A) is very rare (popmax 0.0017%, nfe) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

CUBN p.Pro1297=

c.3891G>A · VCV4743605

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

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 0.17	GERP -3.5, phastCons 0.023
Overall
CADD	9.508	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0017% European (non-Finnish) · 20/1,179,694 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.0013% 21/1,613,534 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0017%	58,985
African / African-American	0.00134%	74,872

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.Pro1297=
Coding: c.3891G>A
MANE Select: NM_001081
Type: single nucleotide variant
Location: chr10:17041159 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1297: a disulfide bond; the cub 8 domain; a UniProt-annotated variant site (in prochob); a UniProt-annotated variant site (in igs1; decreases strongly the cblif binding affinity); a turn

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 p.Pro1297Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
CUBN p.Pro1297Ser 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.3829+1G>A Pathogenic/Likely pathogenic ★★ same condition
CUBN c.4350+2T>C 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-pro1297 (accessed [today's date]).

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