Is CUBN p.Leu1139= (c.3417A>G) pathogenic?

CUBN p.Leu1139= (c.3417A>G) is classified Benign in CUBN (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-31). Common (popmax 20.7%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Imerslund-Grasbeck syndrome.

What condition is associated with CUBN p.Leu1139= (c.3417A>G)?

CUBN p.Leu1139= (c.3417A>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.Leu1139=

Q: How common is CUBN p.Leu1139= (c.3417A>G) in the general population?

CUBN p.Leu1139= (c.3417A>G) is common (popmax 20.7%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3417A>G · rs1801228 · VCV299490

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 20.7%, sas) — 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 -5.5	GERP -3.8
Overall
CADD	0.492	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 20.7% South Asian · 18,845/91,058 alleles

Filtering AF 20.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.3%

Overall 4.4% 71,064/1,613,820 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	20.7%	5
Amishnot grpmax-eligible	10.1%	10
Ashkenazi Jewishnot grpmax-eligible	9.06%	11
Middle Eastern	8.95%	11
Remaining individualsnot grpmax-eligible	5.15%	19
Finnishnot grpmax-eligible	4.77%	21
European (non-Finnish)	3.36%	30
Admixed American	2.48%	40
East Asian	1.97%	51
African / African-American	0.851%	118

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.Leu1139=
Coding: c.3417A>G
MANE Select: NM_001081
dbSNP: rs1801228
Type: single nucleotide variant
Location: chr10:17046007 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1139: the cub 6 domain; a β-strand

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-leu1139 (accessed [today's date]).

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