Is SPG11 p.Leu2326Val (c.6976C>G) pathogenic?

SPG11 p.Leu2326Val (c.6976C>G) is classified Uncertain significance in SPG11 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0692); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary spastic paraplegia 11.

What condition is associated with SPG11 p.Leu2326Val (c.6976C>G)?

SPG11 p.Leu2326Val (c.6976C>G) is associated with hereditary spastic paraplegia 11 (ClinVar).

How common is SPG11 p.Leu2326Val (c.6976C>G) in the general population?

SPG11 p.Leu2326Val (c.6976C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Autosomal recessive spastic paraplegia type 11 inherited?

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

What do computational predictors say about SPG11 p.Leu2326Val (c.6976C>G)?

AlphaMissense predicts likely benign (score 0.0692) — an in-silico prediction, not a clinical call.

SPG11 p.Leu2326Val

c.6976C>G · VCV3671357

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0692 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 11

Computational evidence

Protein change
AlphaMissense	0.0692	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.5	GERP -3
Regional constraint	o/e 1.08	unconstrained · MANE · 101 kb · p 6.8e-06 · regional, not allelic
Overall
CADD	0.792	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.2e-05% 1/1,614,112 alleles · very rare exomes 1/1,461,814 · genomes 0/152,298 · joint denominator

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: SPG11
Protein: p.Leu2326Val
Coding: c.6976C>G
MANE Select: NM_025137
Type: single nucleotide variant
Location: chr15:44565877 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.06 · 3 PDB

Full SPG11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 11 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Portugal)

Similar variants

SPG11 p.Leu2326Pro Uncertain significance ★ ⚠ same residue
SPG11 p.Leu2326= Likely benign ★ same residue
SPG11 c.1457-2A>G Pathogenic/Likely pathogenic ★★ same condition
SPG11 c.1602+1G>A Likely pathogenic ★★ same condition
SPG11 c.1891+1G>T Pathogenic/Likely pathogenic ★★ same condition
SPG11 c.2316+1G>A Pathogenic/Likely pathogenic ★★ same condition
SPG11 c.2317-13C>G Pathogenic/Likely pathogenic ★★ same condition
SPG11 c.2444+1G>A 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/spg11-p-leu2326val (accessed [today's date]).

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