# NM_001063.4(TF):c.1429G>C (p.Ala477Pro)

https://sugi.bio/variant/tf-p-ala477pro

## Summary

**TF p.Ala477Pro (c.1429G>C)** is classified **Pathogenic** in TF (ClinVar, No assertion criteria, 1 submitter; last evaluated 2000-12-15). AlphaMissense: likely pathogenic (0.9544); Very rare (popmax 0.000124%); Associated with atransferrinemia.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs121918679 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000124%)

## For patients & families {#patients}

This is a change in the TF gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to atransferrinemia.

*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, Infancy |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TF is a diagnostic-grade gene on 3 Genomics England panels |

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

- Anemia — Very frequent (99-80%)
- Recurrent infections — Frequent (79-30%)
- Hypothyroidism — Occasional (29-5%)
- Arthritis — Occasional (29-5%)
- Abnormality of the cardiovascular system — Occasional (29-5%)
- Abnormality of the pancreas — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009595/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TF](https://sugi.bio/atlas/gene/TF/) |
| Protein change (HGVS p.) | p.Ala477Pro |
| Coding change (HGVS c.) | c.1429G>C |
| MANE Select transcript | [NM_001063](https://www.ncbi.nlm.nih.gov/nuccore/NM_001063) |
| dbSNP | [rs121918679](https://www.ncbi.nlm.nih.gov/snp/rs121918679/) |
| Variant type | single nucleotide variant |
| Location | chr3:133766376-133766376 (GRCh38) |
| ClinVar | [VCV12620](https://www.ncbi.nlm.nih.gov/clinvar/variation/12620/) |

**All HGVS expressions:** `NC_000003.11:g.133485220G>C`, `NC_000003.12:g.133766376G>C`, `NG_013080.2:g.109379G>C`, `NM_001063.4:c.1429G>C`, `NM_001354703.2:c.1297G>C`, `NM_001354704.2:c.1048G>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9544) — concordant with the pathogenic call
- REVEL 0.64 (indeterminate)
- SaProt LLR -15.79 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 9.901, GERP 1.17, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in TF (of 4,116 modeled).
- CADD: **PHRED 26.4**. 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 0.85** across the covering region of the MANE Select transcript (133,746,441–133,778,617), spanning 32,176 bp. Chi-square p 8.3e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for TF (955 scored positions, the nearest 34 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): global (via dbSNP) **0.000124%** · 2/1,614,224 alleles overall — very rare (popmax 0.000124%).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,512 |

Ashkenazi Jewish 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}

**TF** population constraint: LOEUF 0.834, pLI 1.0745e-12, missense-Z 2.0561. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **atransferrinemia** — Moderate (AR)

## Protein context {#protein}

Residue **477** lies in an α-helix; a binding site; the transferrin-like 2 domain; a UniProt-annotated variant site (in atraf).

AlphaFold model confidence (whole protein): pLDDT 93.39, 86% of residues very-high.

**69 experimental structure(s)** (PDB): [1A8E](https://www.rcsb.org/structure/1A8E), [1A8F](https://www.rcsb.org/structure/1A8F), [1B3E](https://www.rcsb.org/structure/1B3E), [1BP5](https://www.rcsb.org/structure/1BP5), [1BTJ](https://www.rcsb.org/structure/1BTJ), [1D3K](https://www.rcsb.org/structure/1D3K) — incl. mutant structure 1DTG.

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

*Describes the biological roles of TF (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:** TF's established molecular role includes ferrous iron binding. p.Ala477Pro falls in the transferrin-like 2 domain.


### Pathways affected {#pathways}

TF participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [Iron uptake and transport](https://reactome.org/content/detail/R-HSA-917937) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Transferrin endocytosis and recycling](https://reactome.org/content/detail/R-HSA-917977) | curated |

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

**Molecular function:** ferrous iron binding, enzyme binding, iron chaperone activity, transmembrane transporter binding, transferrin receptor binding.

**Biological process:** iron ion transport, intracellular iron ion homeostasis, cell surface receptor signaling pathway, positive regulation of proteasomal ubiquitin-dependent protein catabolic process, positive regulation of receptor-mediated endocytosis, multicellular organismal-level iron ion homeostasis.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2000-12-15.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2000-12-15 |

## Associated conditions {#conditions}

[atransferrinemia](https://sugi.bio/atlas/disease/atransferrinemia/).

**Reported phenotype names (ClinVar):** Atransferrinemia, Familial hypotransferrinemia.

## Similar variants {#similar}

Related TF variant pages (same residue, condition, or type): [TF p.Ala477=](/variant/tf-p-ala477), [TF c.-18C>T](/variant/tf-c-minus-18c-t), [TF p.Ala72Val](/variant/tf-p-ala72val), [TF p.Gln264Glu](/variant/tf-p-gln264glu), [TF p.Ile229Thr](/variant/tf-p-ile229thr), [TF p.Thr112Ala](/variant/tf-p-thr112ala), [TF p.Val451Ala](/variant/tf-p-val451ala), [TF c.1688-4C>A](/variant/tf-c-1688-minus-4c-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 12620). 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.*