Is CUBN p.Pro3525= (c.10575C>T) pathogenic?

CUBN p.Pro3525= (c.10575C>T) is classified Conflicting classifications of pathogenicity in CUBN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-20). Rare (popmax 0.103%, nfe); Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Pro3525= (c.10575C>T)?

CUBN p.Pro3525= (c.10575C>T) is associated with Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome (ClinVar).

How common is CUBN p.Pro3525= (c.10575C>T) in the general population?

CUBN p.Pro3525= (c.10575C>T) is rare (popmax 0.103%, nfe) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

CUBN p.Pro3525=

c.10575C>T · rs145569358 · VCV695982

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.103%, 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 -3.8	GERP -3.7
Overall
CADD	0.096	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.103% European (non-Finnish) · 1,219/1,180,030 alleles

Filtering AF 0.0984% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0965%

Overall 0.0988% 1,595/1,614,026 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.347%	288
European (non-Finnish)grpmax	0.103%	968
South Asian	0.0966%	1,035
Remaining individualsnot grpmax-eligible	0.0736%	1,358
Middle Eastern	0.0657%	1,521
Admixed American	0.0117%	8,571
African / African-American	0.00934%	10,701
East Asian	0.00446%	22,443

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro3525=
Coding: c.10575C>T
MANE Select: NM_001081
dbSNP: rs145569358
Type: single nucleotide variant
Location: chr10:16828994 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3525: a disulfide bond; a UniProt-annotated variant site (in prochob); the cub 27 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 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-pro3525 (accessed [today's date]).

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