Is CUBN p.Pro2554= (c.7662A>G) pathogenic?

CUBN p.Pro2554= (c.7662A>G) is classified Benign/Likely benign in CUBN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). Common (popmax 19%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Pro2554= (c.7662A>G)?

CUBN p.Pro2554= (c.7662A>G) is associated with Imerslund-Grasbeck syndrome, Imerslund-Grasbeck syndrome type 1 (ClinVar).

How is Imerslund-Gräsbeck syndrome inherited?

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

CUBN p.Pro2554=

Q: How common is CUBN p.Pro2554= (c.7662A>G) in the general population?

CUBN p.Pro2554= (c.7662A>G) is common (popmax 19%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.7662A>G · rs3740165 · VCV299420

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 19%, afr) — too common for a highly-penetrant pathogenic allele

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 -15	GERP -3.1
Overall
CADD	0.012	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 19% African / African-American · 14,275/74,998 alleles

Filtering AF 18.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.7%

Overall 4.59% 74,004/1,614,024 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	19%	5
East Asian	15.9%	6
Middle Eastern	6.46%	15
Remaining individualsnot grpmax-eligible	5.43%	18
South Asian	4.61%	22
Ashkenazi Jewishnot grpmax-eligible	4.04%	25
Finnishnot grpmax-eligible	3.51%	28
European (non-Finnish)	3.32%	30
Admixed American	3.29%	30
Amishnot grpmax-eligible	1.21%	83

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.Pro2554=
Coding: c.7662A>G
MANE Select: NM_001081
dbSNP: rs3740165
Type: single nucleotide variant
Location: chr10:16907551 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2554: a UniProt-annotated variant site (in prochob); the cub 18 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-pro2554 (accessed [today's date]).

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