Is CUBN p.Pro321= (c.963C>T) pathogenic?

CUBN p.Pro321= (c.963C>T) is classified Benign/Likely benign in CUBN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.91%, afr); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Pro321= (c.963C>T)?

CUBN p.Pro321= (c.963C>T) is associated with Imerslund-Grasbeck syndrome, Imerslund-Grasbeck syndrome type 1 (ClinVar).

How common is CUBN p.Pro321= (c.963C>T) in the general population?

CUBN p.Pro321= (c.963C>T) is low-frequency (popmax 1.91%, afr) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

CUBN p.Pro321=

c.963C>T · rs150309054 · VCV299532

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.91%, afr)

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.2	GERP -3.2, phastCons 0.073
Overall
CADD	8.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.91% African / African-American · 1,435/75,042 alleles

Filtering AF 1.83% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.8%

Overall 0.126% 2,031/1,614,194 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.91%	52
Ashkenazi Jewishnot grpmax-eligible	0.351%	285
Middle Eastern	0.247%	404
Admixed American	0.188%	531
Remaining individualsnot grpmax-eligible	0.149%	672
European (non-Finnish)	0.0221%	4,521
Finnishnot grpmax-eligible	0.00625%	16,009
East Asian	0.00446%	22,444
South Asian	0.00439%	22,772

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.Pro321=
Coding: c.963C>T
MANE Select: NM_001081
dbSNP: rs150309054
Type: single nucleotide variant
Location: chr10:17110971 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 321: the egf-like 4; calcium-binding 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 p.Pro321Ser Uncertain significance ★★ same residue
CUBN p.Pro321Leu 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-pro321 (accessed [today's date]).

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