Is CUBN p.Ser2187= (c.6561G>A) pathogenic?

CUBN p.Ser2187= (c.6561G>A) is classified Benign in CUBN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). Common (popmax 11.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Imerslund-Grasbeck syndrome type 1.

What condition is associated with CUBN p.Ser2187= (c.6561G>A)?

CUBN p.Ser2187= (c.6561G>A) is associated with Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome (ClinVar).

How is Imerslund-Gräsbeck syndrome inherited?

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

CUBN p.Ser2187=

Q: How common is CUBN p.Ser2187= (c.6561G>A) in the general population?

CUBN p.Ser2187= (c.6561G>A) is common (popmax 11.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6561G>A · rs11254278 · VCV299436

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 11.9%, eas) — too common for a highly-penetrant pathogenic allele

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 -8.2	GERP -3.7
Overall
CADD	1.987	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.9% East Asian · 5,336/44,846 alleles

Filtering AF 11.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.5%

Overall 1.24% 19,994/1,613,734 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	11.9%	8
South Asian	3.03%	33
Finnishnot grpmax-eligible	1.57%	64
Remaining individualsnot grpmax-eligible	1.45%	69
European (non-Finnish)	0.806%	124
African / African-American	0.405%	247
Admixed American	0.267%	375
Middle Eastern	0.264%	379
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867

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.Ser2187=
Coding: c.6561G>A
MANE Select: NM_001081
dbSNP: rs11254278
Type: single nucleotide variant
Location: chr10:16925326 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2187: a UniProt-annotated variant site (in prochob); the cub 15 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 p.Ser2187Leu 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
CUBN c.6822-1G>A 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-ser2187 (accessed [today's date]).

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