Is CUBN p.Ser2075= (c.6225G>A) pathogenic?

CUBN p.Ser2075= (c.6225G>A) is classified Benign/Likely benign in CUBN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-29). Rare (popmax 0.623%, afr); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Ser2075= (c.6225G>A)?

CUBN p.Ser2075= (c.6225G>A) is associated with Imerslund-Grasbeck syndrome (ClinVar).

How common is CUBN p.Ser2075= (c.6225G>A) in the general population?

CUBN p.Ser2075= (c.6225G>A) is rare (popmax 0.623%, afr) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

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

CUBN p.Ser2075=

c.6225G>A · rs75737363 · VCV522510

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.623%, afr)

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 -7.1	GERP -3.4
Overall
CADD	1.562	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.623% African / African-American · 467/75,006 alleles

Filtering AF 0.576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.557%

Overall 0.0329% 531/1,613,858 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.623%	161
Remaining individualsnot grpmax-eligible	0.0336%	2,976
Middle Eastern	0.033%	3,028
Admixed American	0.02%	4,998
South Asian	0.00989%	10,116
East Asian	0.00223%	44,874
European (non-Finnish)	0.00161%	62,099

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.Ser2075=
Coding: c.6225G>A
MANE Select: NM_001081
dbSNP: rs75737363
Type: single nucleotide variant
Location: chr10:16928203 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2075: a UniProt-annotated variant site (in prochob); the cub 14 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

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.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
CUBN c.9454+1G>A Likely pathogenic ★★ same condition
CUBN p.Arg1487Ter 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-ser2075 (accessed [today's date]).

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