# NM_001081.4(CUBN):c.735C>T (p.Cys245=)

https://sugi.bio/variant/cubn-p-cys245

## Summary

**CUBN p.Cys245= (c.735C>T)** is classified **Conflicting classifications of pathogenicity** in CUBN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-09). Ultra-rare (popmax 0.018%, nfe); Associated with Imerslund-Grasbeck syndrome type 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs766772944 · 3 submitters · 2 linked conditions · ultra-rare (popmax 0.018%, nfe)

## For patients & families {#patients}

This is a change in the CUBN gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Imerslund-Grasbeck syndrome type 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Finland) |
| Diagnostic panels | CUBN is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Imerslund-Gräsbeck syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased circulating vitamin B12 concentration — Obligate (100%)
- Malabsorption of Vitamin B12 — Obligate (100%)
- Abnormal blood 5-methyltetrahydrofolate level — Obligate (100%)
- Megaloblastic anemia — Very frequent (99-80%)
- Macrocytic anemia — Very frequent (99-80%)
- Hypersegmentation of neutrophil nuclei — Very frequent (99-80%)
- Proteinuria — Frequent (79-30%)
- Pallor — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026066/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CUBN](https://sugi.bio/atlas/gene/CUBN/) |
| Protein change (HGVS p.) | p.Cys245= |
| Coding change (HGVS c.) | c.735C>T |
| MANE Select transcript | [NM_001081](https://www.ncbi.nlm.nih.gov/nuccore/NM_001081) |
| dbSNP | [rs766772944](https://www.ncbi.nlm.nih.gov/snp/rs766772944/) |
| Variant type | single nucleotide variant |
| Location | chr10:17114175-17114175 (GRCh38) |
| ClinVar | [VCV299540](https://www.ncbi.nlm.nih.gov/clinvar/variation/299540/) |

**All HGVS expressions:** `LRG_540:g.20643C>T`, `LRG_540t1:c.735C>T`, `NC_000010.10:g.17156174G>A`, `NC_000010.11:g.17114175G>A`, `NG_008967.1:g.20643C>T`, `NM_001081.4:c.735C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 2.141, GERP 1.08, phastCons 0.99 — highly conserved position (PP3-type support)
- CADD: **PHRED 8.788**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.23 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.018%** (nfe) · FAF95 0.016% · FAF99 0.0151% · 212/1,179,920 in the highest group · 242/1,613,670 alleles overall — ultra-rare (popmax 0.018%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0448% | 2,231 |
| European (non-Finnish) (grpmax) | 0.018% | 5,566 |
| African / African-American | 0.00133% | 74,918 |
| South Asian | 0.0011% | 90,916 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CUBN** population constraint: LOEUF 0.756, pLI 1.0686e-57, missense-Z 1.0005; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


**2 experimental structure(s)** (PDB): [3KQ4](https://www.rcsb.org/structure/3KQ4), [6GJE](https://www.rcsb.org/structure/6GJE).

## What this gene does {#gene-function}

*Describes the biological roles of CUBN (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CUBN's established molecular role includes cargo receptor activity. In Reactome, CUBN is annotated in disease pathway(s) including **Defective AMN causes MGA1**, **Defective CUBN causes MGA1**.

**Disease mechanism (Reactome):** CUBN loss or alteration is curated in [Defective AMN causes MGA1](https://reactome.org/content/detail/R-HSA-3359462), [Defective CUBN causes MGA1](https://reactome.org/content/detail/R-HSA-3359463).

### Pathways affected {#pathways}

CUBN participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective AMN causes MGA1](https://reactome.org/content/detail/R-HSA-3359462) | curated |
| ⚕ [Defective CUBN causes MGA1](https://reactome.org/content/detail/R-HSA-3359463) | curated |
| [HDL clearance](https://reactome.org/content/detail/R-HSA-8964011) | curated |
| [Uptake of dietary cobalamins into enterocytes](https://reactome.org/content/detail/R-HSA-9758881) | curated |
| [Vitamin D (calciferol) metabolism](https://reactome.org/content/detail/R-HSA-196791) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** cargo receptor activity, protein homodimerization activity.

**Biological process:** cobalamin metabolic process, cobalamin transport.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-12-09.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-09 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-01 |

## Associated conditions {#conditions}

[Imerslund-Grasbeck syndrome type 1](https://sugi.bio/atlas/disease/imerslund-grasbeck-syndrome-type-1/), [Imerslund-Grasbeck syndrome](https://sugi.bio/atlas/disease/imerslund-grasbeck-syndrome/).

**Reported phenotype names (ClinVar):** Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome, not provided, none provided, Megaloblastic anemia 1, Finnish type, MEGALOBLASTIC ANEMIA, 1, Imerslund-Gräsbeck syndrome 1, Megaloblastic anemia due to inborn errors of metabolism, Imerslund-Gräsbeck syndrome, ENTEROCYTE COBALAMIN MALABSORPTION.

## Similar variants {#similar}

Related CUBN variant pages (same residue, condition, or type): [CUBN c.10033-1G>A](/variant/cubn-c-10033-minus-1g-a), [CUBN c.1230+1G>A](/variant/cubn-c-1230-plus-1g-a), [CUBN c.3672+2T>C](/variant/cubn-c-3672-plus-2t-c), [CUBN c.3829+1G>A](/variant/cubn-c-3829-plus-1g-a), [CUBN c.4350+2T>C](/variant/cubn-c-4350-plus-2t-c), [CUBN c.6821+3A>G](/variant/cubn-c-6821-plus-3a-g), [CUBN c.6822-1G>A](/variant/cubn-c-6822-minus-1g-a), [CUBN c.8598+1G>T](/variant/cubn-c-8598-plus-1g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 299540). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*