# NM_001063.4(TF):c.1274C>T (p.Pro425Leu)

https://sugi.bio/variant/tf-p-pro425leu

## Summary

**TF p.Pro425Leu (c.1274C>T)** is classified **Uncertain significance** in TF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). AlphaMissense: likely pathogenic (0.6806); Very rare (popmax 0.0011%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the TF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [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.Pro425Leu |
| Coding change (HGVS c.) | c.1274C>T |
| MANE Select transcript | [NM_001063](https://www.ncbi.nlm.nih.gov/nuccore/NM_001063) |
| Variant type | single nucleotide variant |
| Location | chr3:133764252-133764252 (GRCh38) |
| ClinVar | [VCV4701919](https://www.ncbi.nlm.nih.gov/clinvar/variation/4701919/) |

**All HGVS expressions:** `NC_000003.11:g.133483096C>T`, `NC_000003.12:g.133764252C>T`, `NG_013080.2:g.107255C>T`, `NG_013080.3:g.107256C>T`, `NM_001063.4:c.1274C>T`, `NM_001354703.2:c.1142C>T`, `NM_001354704.2:c.893C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6806)
- REVEL 0.66 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -17.275 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 4.71, GERP 2.16, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 31.0**. 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). 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. This allele is not in the release, so all four of its deltas are under 0.2. 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, and here that is proven rather than inferred: a different substitution at this very position, C>G, IS in the release and scores Δ0.32 donor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *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): grpmax **0.0011%** (sas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/91,076 in the highest group · 4/1,613,942 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,076 |
| European (non-Finnish) | 0.000254% | 393,283 |

*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 **425** lies in a β-strand; the transferrin-like 2 domain.

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.Pro425Leu 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-12.

**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 | 2025-11-12 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related TF variant pages (same residue, condition, or type): [TF c.-18C>T](/variant/tf-c-minus-18c-t), [TF p.Ala318Ser](/variant/tf-p-ala318ser), [TF p.Ala72Val](/variant/tf-p-ala72val), [TF p.Gln264Glu](/variant/tf-p-gln264glu), [TF p.Gln559Leu](/variant/tf-p-gln559leu), [TF p.Ile229Thr](/variant/tf-p-ile229thr), [TF p.Thr112Ala](/variant/tf-p-thr112ala), [TF p.Val270Asp](/variant/tf-p-val270asp).

### 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 4701919). 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.*