# NM_000601.6(HGF):c.76A>G (p.Ile26Val)

https://sugi.bio/variant/hgf-p-ile26val

## Summary

**HGF p.Ile26Val (c.76A>G)** is classified **Uncertain significance** in HGF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-02). AlphaMissense: likely benign (0.0708); No allele count reported in gnomAD v4.1 (AN 1,566,400).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · no allele count reported in gnomAD v4.1 (AN 1,566,400)

## For patients & families {#patients}

This is a change in the HGF 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 | [HGF](https://sugi.bio/atlas/gene/HGF/) |
| Protein change (HGVS p.) | p.Ile26Val |
| Coding change (HGVS c.) | c.76A>G |
| MANE Select transcript | [NM_000601](https://www.ncbi.nlm.nih.gov/nuccore/NM_000601) |
| Variant type | single nucleotide variant |
| Location | chr7:81769896-81769896 (GRCh38) |
| ClinVar | [VCV3776406](https://www.ncbi.nlm.nih.gov/clinvar/variation/3776406/) |

**All HGVS expressions:** `NC_000007.13:g.81399212T>C`, `NC_000007.14:g.81769896T>C`, `NG_016274.2:g.5241A>G`, `NM_000601.6:c.76A>G`, `NM_001010931.3:c.76A>G`, `NM_001010932.3:c.76A>G`, `NM_001010933.3:c.76A>G`, `NM_001010934.3:c.76A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0708)
- REVEL 0.07 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.709 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.537, GERP 0.272, phastCons 1 — weakly conserved position
- CADD: **PHRED 12.76**. 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 0.81** across the covering region of the MANE Select transcript (81,706,404–81,769,971), spanning 63,567 bp. Chi-square p 4.1e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,566,400)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**HGF** population constraint: LOEUF 0.471, pLI 0.99627, missense-Z 1.9628. *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):

- **nonsyndromic genetic hearing loss** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.76, 52% of residues very-high.

**36 experimental structure(s)** (PDB): [1BHT](https://www.rcsb.org/structure/1BHT), [1GMN](https://www.rcsb.org/structure/1GMN), [1GMO](https://www.rcsb.org/structure/1GMO), [1GP9](https://www.rcsb.org/structure/1GP9), [1NK1](https://www.rcsb.org/structure/1NK1), [1SHY](https://www.rcsb.org/structure/1SHY) — incl. mutant structure 1GP9.

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

*Describes the biological roles of HGF (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:** HGF's established molecular role includes chemoattractant activity. In Reactome, HGF is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**.

**Disease mechanism (Reactome):** HGF loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530).

### Pathways affected {#pathways}

HGF participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| [Drug-mediated inhibition of MET activation](https://reactome.org/content/detail/R-HSA-9734091) | curated |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [MET Receptor Activation](https://reactome.org/content/detail/R-HSA-6806942) | curated |
| [MET activates PI3K/AKT signaling](https://reactome.org/content/detail/R-HSA-8851907) | curated |
| [MET activates PTK2 signaling](https://reactome.org/content/detail/R-HSA-8874081) | curated |
| [MET activates PTPN11](https://reactome.org/content/detail/R-HSA-8865999) | curated |
| [MET activates RAP1 and RAC1](https://reactome.org/content/detail/R-HSA-8875555) | curated |
| [MET activates RAS signaling](https://reactome.org/content/detail/R-HSA-8851805) | curated |
| [MET activates STAT3](https://reactome.org/content/detail/R-HSA-8875791) | curated |
| [MET interacts with TNS proteins](https://reactome.org/content/detail/R-HSA-8875513) | curated |
| [MET receptor recycling](https://reactome.org/content/detail/R-HSA-8875656) | curated |
| [Negative regulation of MET activity](https://reactome.org/content/detail/R-HSA-6807004) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Interleukin-7 signaling](https://reactome.org/content/detail/R-HSA-1266695) | electronic |

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

**Molecular function:** chemoattractant activity, identical protein binding.

**Biological process:** positive regulation of cell migration, cellular response to hepatocyte growth factor stimulus, positive regulation of MAPK cascade, hepatocyte growth factor receptor signaling pathway, positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction, cell chemotaxis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-02 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related HGF variant pages (same residue, condition, or type): [HGF p.Ala432Val](/variant/hgf-p-ala432val), [HGF p.Ala661Thr](/variant/hgf-p-ala661thr), [HGF p.Arg168Trp](/variant/hgf-p-arg168trp), [HGF p.Arg220Gln](/variant/hgf-p-arg220gln), [HGF p.Arg242Gln](/variant/hgf-p-arg242gln), [HGF p.Arg242Trp](/variant/hgf-p-arg242trp), [HGF p.Arg328His](/variant/hgf-p-arg328his), [HGF p.Arg350Gln](/variant/hgf-p-arg350gln).

### 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 3776406). 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.*