# NM_001081.4(CUBN):c.4987T>C (p.Ser1663Pro)

https://sugi.bio/variant/cubn-p-ser1663pro

## Summary

**CUBN p.Ser1663Pro (c.4987T>C)** is classified **Uncertain significance** in CUBN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-27). AlphaMissense: likely pathogenic (0.8433); Absent from gnomAD v4.1; Associated with Imerslund-Grasbeck syndrome type 1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CUBN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Ser1663Pro |
| Coding change (HGVS c.) | c.4987T>C |
| MANE Select transcript | [NM_001081](https://www.ncbi.nlm.nih.gov/nuccore/NM_001081) |
| Variant type | single nucleotide variant |
| Location | chr10:16950094-16950094 (GRCh38) |
| ClinVar | [VCV3593132](https://www.ncbi.nlm.nih.gov/clinvar/variation/3593132/) |

**All HGVS expressions:** `LRG_540:g.184724T>C`, `LRG_540t1:c.4987T>C`, `NC_000010.10:g.16992093A>G`, `NC_000010.11:g.16950094A>G`, `NG_008967.1:g.184724T>C`, `NM_001081.4:c.4987T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8433)
- REVEL 0.353 (indeterminate)
- Conservation: phyloP 6.094, GERP 1.84, phastCons 1 — highly conserved (agrees)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- AlphaMissense ranks this among the **top 9%** most-pathogenic-predicted substitutions in CUBN (of 21,413 modeled).
- CADD: **PHRED 25.8**. 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.*
- Regional missense constraint: **o/e 1.05** across the covering region of the MANE Select transcript (16,906,245–16,990,508), spanning 84,263 bp. Chi-square p 0.074. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **1663** lies in a UniProt-annotated variant site (in prochob); the cub 11 domain.

**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. p.Ser1663Pro falls in the cub 11 domain. 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Imerslund-Grasbeck syndrome type 1, Proteinuria, chronic benign, MEGALOBLASTIC ANEMIA, 1, Megaloblastic anemia 1, Finnish type, Imerslund-Gräsbeck syndrome 1.

## Similar variants {#similar}

Related CUBN variant pages (same residue, condition, or type): [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.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), [CUBN c.9454+1G>A](/variant/cubn-c-9454-plus-1g-a), [CUBN p.Arg1487Ter](/variant/cubn-p-arg1487ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 3593132). 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.*