Is SPG11 p.Leu26Val (c.76C>G) pathogenic?

SPG11 p.Leu26Val (c.76C>G) is classified Uncertain significance in SPG11 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-21). AlphaMissense: likely benign (0.1882); Very rare (popmax 8.52e-05%, nfe); Associated with hereditary spastic paraplegia 11.

What condition is associated with SPG11 p.Leu26Val (c.76C>G)?

SPG11 p.Leu26Val (c.76C>G) is associated with hereditary spastic paraplegia 11 (ClinVar).

How common is SPG11 p.Leu26Val (c.76C>G) in the general population?

SPG11 p.Leu26Val (c.76C>G) is very rare (popmax 8.52e-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.Leu26Val (c.76C>G)?

AlphaMissense predicts likely benign (score 0.1882) — an in-silico prediction, not a clinical call.

SPG11 p.Leu26Val

c.76C>G · rs778824072 · VCV2051770

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1882 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 11

Computational evidence

Protein change
AlphaMissense	0.1882	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -6.84	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 0.76	GERP -3.3, phastCons 0.23
Regional constraint	o/e 1.08	unconstrained · MANE · 101 kb · p 6.8e-06 · regional, not allelic
Overall
CADD	17.92	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 8.52e-05% European (non-Finnish) · 1/1,173,836 alleles

Overall 0.000814% 13/1,596,890 alleles · very rare exomes 13/1,444,508 · genomes 0/152,382 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0137%	7,295
Remaining individualsnot grpmax-eligible	0.00647%	15,466
European (non-Finnish)grpmax	8.52e-05%	1,173,836

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu26Val
Coding: c.76C>G
MANE Select: NM_025137
dbSNP: rs778824072
Type: single nucleotide variant
Location: chr15:44663572 (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.Leu26Pro Uncertain significance ★★ ⚠ same residue
SPG11 p.Leu26= 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-leu26val (accessed [today's date]).

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