Is SPG7 p.Leu725= (c.2173T>C) pathogenic?

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.

What condition is associated with SPG7 p.Leu725= (c.2173T>C)?

SPG7 p.Leu725= (c.2173T>C) is associated with hereditary spastic paraplegia 7 (ClinVar).

How common is SPG7 p.Leu725= (c.2173T>C) in the general population?

SPG7 p.Leu725= (c.2173T>C) is very rare (popmax 0.000594%, nfe) (gnomAD).

How is Spastic paraplegia type 7 inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SPG7 p.Leu725=

c.2173T>C · rs1365235920 · VCV2189974

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Conditions

hereditary spastic paraplegia 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.87 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.77	GERP -0.6, phastCons 1
Overall
CADD	10.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000594% European (non-Finnish) · 7/1,179,372 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000435% 7/1,607,816 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SPG7
Protein: p.Leu725=
Coding: c.2173T>C
MANE Select: NM_003119
dbSNP: rs1365235920
Type: single nucleotide variant
Location: chr16:89554555 (GRCh38)
Gene constraint: LOEUF 1.547 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.10 · 2 PDB
Residue 725: the 'interaction with ppif' region

Full SPG7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spastic paraplegia type 7 (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly

Similar variants

SPG7 c.1324+2T>G Pathogenic/Likely pathogenic ★★ same condition
SPG7 c.1552+1G>T Pathogenic/Likely pathogenic ★★ same condition
SPG7 c.1553-2A>G Pathogenic/Likely pathogenic ★★ same condition
SPG7 c.1779+1G>T Pathogenic/Likely pathogenic ★★ same condition
SPG7 c.1936+2T>A Likely pathogenic ★★ same condition
SPG7 c.1937-2A>G Pathogenic ★★ same condition
SPG7 c.2104-2A>G Pathogenic/Likely pathogenic ★★ same condition
SPG7 c.286+1G>T Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/spg7-p-leu725 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown