# NM_003119.4(SPG7):c.2173T>C (p.Leu725=)

https://sugi.bio/variant/spg7-p-leu725

## Summary

**SPG7 p.Leu725= (c.2173T>C)** is classified **Likely benign** in SPG7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-28). Very rare (popmax 0.000594%, nfe); Associated with hereditary spastic paraplegia 7.

**At a glance:** Likely benign · review: Single submitter · rsID rs1365235920 · 1 submitter · 1 linked condition · very rare (popmax 0.000594%, nfe)

## For patients & families {#patients}

This is a change in the SPG7 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to hereditary spastic paraplegia 7.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Elderly |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SPG7 is a diagnostic-grade gene on 21 Genomics England panels |

**Commonly reported features of Spastic paraplegia type 7** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Spastic gait — Very frequent (99-80%)
- Urinary urgency — Frequent (79-30%)
- Supranuclear gaze palsy — Frequent (79-30%)
- Nystagmus — Frequent (79-30%)
- Optic atrophy — Frequent (79-30%)
- Cerebellar atrophy — Frequent (79-30%)
- Hypernasal speech — Frequent (79-30%)
- Impaired vibration sensation in the lower limbs — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004927/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SPG7](https://sugi.bio/atlas/gene/SPG7/) |
| Protein change (HGVS p.) | p.Leu725= |
| Coding change (HGVS c.) | c.2173T>C |
| MANE Select transcript | [NM_003119](https://www.ncbi.nlm.nih.gov/nuccore/NM_003119) |
| dbSNP | [rs1365235920](https://www.ncbi.nlm.nih.gov/snp/rs1365235920/) |
| Variant type | single nucleotide variant |
| Location | chr16:89554555-89554555 (GRCh38) |
| ClinVar | [VCV2189974](https://www.ncbi.nlm.nih.gov/clinvar/variation/2189974/) |

**All HGVS expressions:** `NC_000016.10:g.89554555T>C`, `NC_000016.9:g.89620963T>C`, `NG_008082.1:g.51159T>C`, `NM_001363850.1:c.2173T>C`, `NM_003119.4:c.2173T>C`

## 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 0.769, GERP -0.596, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 10.2**. 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 (T>G, Δ0.87 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 **0.000594%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,179,372 in the highest group · 7/1,607,816 alleles overall — very rare (popmax 0.000594%, nfe).

*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}

**SPG7** population constraint: LOEUF 1.547, pLI 1.8134e-39, missense-Z -1.4984; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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):

- **mitochondrial disease** — Disputed (AD)
- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}

Residue **725** lies in the 'interaction with ppif' region.

AlphaFold model confidence (whole protein): pLDDT 74.10, 29% of residues very-high.

**2 experimental structure(s)** (PDB): [2QZ4](https://www.rcsb.org/structure/2QZ4), [9RK6](https://www.rcsb.org/structure/9RK6).

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

*Describes the biological roles of SPG7 (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:** SPG7's established molecular role includes metalloendopeptidase activity. p.Leu725= falls in the interaction with ppif region.


### Pathways affected {#pathways}

SPG7 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |
| [Processing of SMDT1](https://reactome.org/content/detail/R-HSA-8949664) | curated |

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

**Molecular function:** metalloendopeptidase activity.

**Biological process:** mitochondrial protein processing, regulation of mitochondrial membrane permeability, regulation of calcium import into the mitochondrion, mitochondrial outer membrane permeabilization involved in programmed cell death.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-28.

**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 | 2022-06-28 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 7](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-7/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 7, Spastic paraplegia 7, Hereditary spastic paraplegia Paraplegin type, SPG7-related neurologic disorder, SPASTIC PARAPLEGIA 7, AUTOSOMAL RECESSIVE, WITH OR WITHOUT CEREBELLAR ATAXIA, Autosomal recessive spastic paraplegia type 7.

## Similar variants {#similar}

Related SPG7 variant pages (same residue, condition, or type): [SPG7 c.1324+2T>G](/variant/spg7-c-1324-plus-2t-g), [SPG7 c.1552+1G>T](/variant/spg7-c-1552-plus-1g-t), [SPG7 c.1553-2A>G](/variant/spg7-c-1553-minus-2a-g), [SPG7 c.1779+1G>T](/variant/spg7-c-1779-plus-1g-t), [SPG7 c.1936+2T>A](/variant/spg7-c-1936-plus-2t-a), [SPG7 c.1937-2A>G](/variant/spg7-c-1937-minus-2a-g), [SPG7 c.2104-2A>G](/variant/spg7-c-2104-minus-2a-g), [SPG7 c.286+1G>T](/variant/spg7-c-286-plus-1g-t).

### 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 2026-07-14); 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 2189974). 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.*