# NM_005142.3(CBLIF):c.1211C>G (p.Pro404Arg)

https://sugi.bio/variant/cblif-p-pro404arg

## Summary

**CBLIF p.Pro404Arg (c.1211C>G)** is classified **Uncertain significance** in CBLIF (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-26). AlphaMissense: likely pathogenic (0.8873); Very rare (popmax 8.5e-05%, nfe); Associated with hereditary intrinsic factor deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1460997213 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.5e-05%, nfe)

## For patients & families {#patients}

This is a change in the CBLIF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to hereditary intrinsic factor deficiency.

*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, Not applicable |
| Age of onset (of this condition) | Childhood |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CBLIF is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Congenital intrinsic factor deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Absence of intrinsic factor — Obligate (100%)
- Megaloblastic anemia — Very frequent (99-80%)
- Decreased circulating vitamin B12 concentration — Very frequent (99-80%)
- Dementia — Frequent (79-30%)
- Specific learning disability — Frequent (79-30%)
- Hyperhomocystinemia — Frequent (79-30%)
- Recurrent infections — Frequent (79-30%)
- Methylmalonic acidemia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003024/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CBLIF](https://sugi.bio/atlas/gene/CBLIF/) |
| Protein change (HGVS p.) | p.Pro404Arg |
| Coding change (HGVS c.) | c.1211C>G |
| MANE Select transcript | [NM_005142](https://www.ncbi.nlm.nih.gov/nuccore/NM_005142) |
| dbSNP | [rs1460997213](https://www.ncbi.nlm.nih.gov/snp/rs1460997213/) |
| Variant type | single nucleotide variant |
| Location | chr11:59829527-59829527 (GRCh38) |
| ClinVar | [VCV1059830](https://www.ncbi.nlm.nih.gov/clinvar/variation/1059830/) |

**All HGVS expressions:** `NC_000011.10:g.59829527G>C`, `NC_000011.9:g.59597000G>C`, `NG_008120.1:g.20975C>G`, `NM_005142.3:c.1211C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.8873)
- REVEL 0.352 (indeterminate)
- SaProt LLR -15.997 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 8.271, GERP 2.04, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in CBLIF (of 2,463 modeled).
- CADD: **PHRED 27.4**. 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 0.94** across the covering region of the MANE Select transcript (59,829,487–59,845,453), spanning 15,966 bp. Chi-square p 0.16. 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 (gnomAD v4.1): grpmax **8.5e-05%** (nfe) · 1/1,176,174 in the highest group · 3/1,609,744 alleles overall — very rare (popmax 8.5e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,360 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,014 |
| European (non-Finnish) (grpmax) | 8.5e-05% | 1,176,174 |

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}

**CBLIF** population constraint: LOEUF 0.865, pLI 0.0051339, missense-Z 0.66559. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.69, 83% of residues very-high.

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

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

*Describes the biological roles of CBLIF (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:** CBLIF's established molecular role includes cobalamin binding. In Reactome, CBLIF is annotated in disease pathway(s) including **Defective AMN causes MGA1**, **Defective CBLIF causes IFD**.

**Disease mechanism (Reactome):** CBLIF loss or alteration is curated in [Defective AMN causes MGA1](https://reactome.org/content/detail/R-HSA-3359462), [Defective CBLIF causes IFD](https://reactome.org/content/detail/R-HSA-3359457), [Defective CUBN causes MGA1](https://reactome.org/content/detail/R-HSA-3359463).

### Pathways affected {#pathways}

CBLIF participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective AMN causes MGA1](https://reactome.org/content/detail/R-HSA-3359462) | curated |
| ⚕ [Defective CBLIF causes IFD](https://reactome.org/content/detail/R-HSA-3359457) | curated |
| ⚕ [Defective CUBN causes MGA1](https://reactome.org/content/detail/R-HSA-3359463) | curated |
| [Uptake of dietary cobalamins into enterocytes](https://reactome.org/content/detail/R-HSA-9758881) | curated |

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

**Molecular function:** cobalamin binding, cargo receptor ligand activity.

**Biological process:** cobalamin transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-12-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-12-26 |

## Associated conditions {#conditions}

[hereditary intrinsic factor deficiency](https://sugi.bio/atlas/disease/hereditary-intrinsic-factor-deficiency/).

**Reported phenotype names (ClinVar):** Hereditary intrinsic factor deficiency, Congenital intrinsic factor deficiency, PERNICIOUS ANEMIA, CONGENITAL, DUE TO DEFECT OF INTRINSIC FACTOR.

## Similar variants {#similar}

Related CBLIF variant pages (same residue, condition, or type): [CBLIF c.79+1G>A](/variant/cblif-c-79-plus-1g-a), [CBLIF p.Ser46Leu](/variant/cblif-p-ser46leu), [CBLIF p.Ala377Thr](/variant/cblif-p-ala377thr), [CBLIF p.Ala377Val](/variant/cblif-p-ala377val), [CBLIF p.Arg104Gln](/variant/cblif-p-arg104gln), [CBLIF p.Arg352Cys](/variant/cblif-p-arg352cys), [CBLIF p.Arg352His](/variant/cblif-p-arg352his), [CBLIF p.Gln351Glu](/variant/cblif-p-gln351glu).

### 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 1059830). 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.*