Is SPG11 p.Ser331= (c.993C>T) pathogenic?

SPG11 p.Ser331= (c.993C>T) is classified Benign in SPG11 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 7.88%, eas) — too common for a highly-penetrant pathogenic allele; Associated with amyotrophic lateral sclerosis type 5.

What condition is associated with SPG11 p.Ser331= (c.993C>T)?

SPG11 p.Ser331= (c.993C>T) is associated with amyotrophic lateral sclerosis type 5, hereditary spastic paraplegia 11, Charcot-Marie-Tooth disease axonal type 2X (ClinVar).

How is Juvenile amyotrophic lateral sclerosis inherited?

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

SPG11 p.Ser331=

Q: How common is SPG11 p.Ser331= (c.993C>T) in the general population?

SPG11 p.Ser331= (c.993C>T) is common (popmax 7.88%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.993C>T · rs76823973 · VCV316110

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 7.88%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

amyotrophic lateral sclerosis type 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.5	GERP -4.3, phastCons 0.99
Overall
CADD	6.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.88% East Asian · 3,536/44,870 alleles

Filtering AF 7.66% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.58%

Overall 0.319% 5,154/1,614,078 alleles · common exomes 4,244/1,461,826 · genomes 910/152,252 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	7.88%	13
African / African-American	0.84%	119
Remaining individualsnot grpmax-eligible	0.83%	120
South Asian	0.405%	247
Admixed American	0.0767%	1,305
Middle Eastern	0.033%	3,029
European (non-Finnish)	0.00441%	22,692

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.Ser331=
Coding: c.993C>T
MANE Select: NM_025137
dbSNP: rs76823973
Type: single nucleotide variant
Location: chr15:44652143 (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

amyotrophic lateral sclerosis type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 11 Charcot-Marie-Tooth disease axonal type 2X hereditary spastic paraplegia

For Juvenile amyotrophic lateral sclerosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

SPG11 p.Ser331Phe Uncertain significance ★★ ⚠ same residue
SPG11 p.Ser331Ala Uncertain significance ★ ⚠ 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-ser331 (accessed [today's date]).

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