# NM_000410.4(HFE):c.765C>T (p.Asp255=)

https://sugi.bio/variant/hfe-p-asp255

## Summary

**HFE p.Asp255= (c.765C>T)** is classified **Likely benign** in HFE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-22). Very rare (popmax 0.00136%, nfe); Associated with hereditary hemochromatosis.

**At a glance:** Likely benign · review: Single submitter · rsID rs777622145 · 1 submitter · 1 linked condition · very rare (popmax 0.00136%, nfe)

## For patients & families {#patients}

This is a change in the HFE gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to hereditary hemochromatosis.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 36 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024434/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HFE](https://sugi.bio/atlas/gene/HFE/) |
| Protein change (HGVS p.) | p.Asp255= |
| Coding change (HGVS c.) | c.765C>T |
| MANE Select transcript | [NM_000410](https://www.ncbi.nlm.nih.gov/nuccore/NM_000410) |
| dbSNP | [rs777622145](https://www.ncbi.nlm.nih.gov/snp/rs777622145/) |
| Variant type | single nucleotide variant |
| Location | chr6:26092833-26092833 (GRCh38) |
| ClinVar | [VCV1654858](https://www.ncbi.nlm.nih.gov/clinvar/variation/1654858/) |

**All HGVS expressions:** `LRG_748:g.10553C>T`, `LRG_748t1:c.765C>T`, `NC_000006.11:g.26093061C>T`, `NC_000006.12:g.26092833C>T`, `NG_008720.2:g.10553C>T`, `NM_000410.4:c.765C>T`, `NM_001300749.3:c.765C>T`, `NM_001384164.1:c.765C>T`, `NM_001406751.1:c.756C>T`, `NM_001406752.1:c.501C>T`, `NM_139003.3:c.447C>T`, `NM_139004.3:c.489C>T`, `NM_139006.3:c.723C>T`, `NM_139007.3:c.501C>T`, `NM_139008.3:c.459C>T`, `NM_139009.3:c.696C>T`, `NM_139010.3:c.225C>T`, `NM_139011.3:c.77-286C>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 -8.342 — fast-evolving / accelerated position
- CADD: **PHRED 1.515**. 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 (C>G, Δ0.84 donor gain), 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 **0.00136%** (nfe) · FAF95 0.000803% · FAF99 0.00065% · 16/1,180,052 in the highest group · 17/1,614,088 alleles overall — very rare (popmax 0.00136%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00136% | 73,753 |
| South Asian | 0.0011% | 91,092 |

*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}

**HFE** population constraint: LOEUF 1.037, pLI 1.0122e-09, missense-Z 1.3712; 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.*

Curated gene–disease validity (ClinGen):

- **hemochromatosis type 1** — Definitive (AR)

## Protein context {#protein}

Residue **255** lies in the ig-like c1-type domain; a β-strand; the 'alpha-3' region.

AlphaFold model confidence (whole protein): pLDDT 88.62, 72% of residues very-high.

**2 experimental structure(s)** (PDB): [1A6Z](https://www.rcsb.org/structure/1A6Z), [1DE4](https://www.rcsb.org/structure/1DE4).

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

*Describes the biological roles of HFE (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:** HFE's established molecular role includes signaling receptor binding. p.Asp255= falls in the ig-like c1-type domain.


### Pathways affected {#pathways}

HFE participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Transferrin endocytosis and recycling](https://reactome.org/content/detail/R-HSA-917977) | curated |

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

**Molecular function:** signaling receptor binding, beta-2-microglobulin binding, co-receptor binding, transporter activator activity, transferrin receptor binding.

**Biological process:** negative regulation of T cell cytokine production, intracellular iron ion homeostasis, receptor-mediated endocytosis, cell surface receptor signaling pathway, response to iron ion, BMP signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-22.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-07-22 |

## Associated conditions {#conditions}

[hereditary hemochromatosis](https://sugi.bio/atlas/disease/hereditary-hemochromatosis/).

**Reported phenotype names (ClinVar):** Hereditary hemochromatosis.

## Same-residue context {#hotspot}

Residue **255** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [HFE p.Asp255fs](/variant/hfe-p-asp255fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related HFE variant pages (same residue, condition, or type): [HFE p.Asp255fs](/variant/hfe-p-asp255fs), [HFE c.1006+1G>A](/variant/hfe-c-1006-plus-1g-a), [HFE c.616+1G>A](/variant/hfe-c-616-plus-1g-a), [HFE c.616+1G>T](/variant/hfe-c-616-plus-1g-t), [HFE c.76+2T>C](/variant/hfe-c-76-plus-2t-c), [HFE p.Gln283Pro](/variant/hfe-p-gln283pro), [HFE p.Glu298Ter](/variant/hfe-p-glu298ter), [HFE p.Leu183Pro](/variant/hfe-p-leu183pro).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1654858). 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.*