chr2-32063962-C-T

Variant names:

• chr2-32063962-C-T
• rs121908515
• NM_014946.4:c.131C>T
• SPAST p.Ser44Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025).

The NM_014946.4(SPAST):c.131C>T (p.Ser44Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00785 (AC=12,656) in the gnomAD database across 1,612,216 control chromosomes, including 71 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00981. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S44= (synonymous): Likely_benign (ClinVar VariationId 2168183, 1 star) The variant has been observed in cBioPortal in 2 samples across 2 studies and 1 cancer type; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (65 hom.)
• Consequence: SPAST NM_014946.4 missense
• Clinical Significance: Benign/Likely benign; other; risk factor criteria provided, multiple submitters, no conflicts B:15 O:4
• Conservation: PhyloP100: 5.07
• Publications: 39 publications found

Genes affected

SPAST (HGNC:11233): (spastin) This gene encodes a member of the AAA (ATPases associated with a variety of cellular activities) protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The use of alternative translational initiation sites in this gene results in a single transcript variant that can produce isoforms that differ in the length of their N-terminus and which thereby differ in the efficiency of their export from the nucleus to the cytoplasm. In addition, alternative splicing results in multiple transcript variants that encode isoforms that differ in other protein regions as well. One isoform of this gene has been shown to be a microtubule-severing enzyme that regulates microtubule abundance, mobility, and plus-end distribution. Mutations in this gene cause the most frequent form of autosomal dominant spastic paraplegia 4. [provided by RefSeq, May 2018]

SPAST Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics, Genomics England PanelApp
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P
• SPAST-related motor disorder

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 20 criteria.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_014946.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SPAST NM_014946.4	MANE Select	c.131C>T p.Ser44Leu	missense	Exon 1 of 17	Prot: NP_055761.2
	SPAST NM_001363823.2		c.131C>T p.Ser44Leu	missense	Exon 1 of 17	Prot: NP_001350752.1 UniProt:
	SPAST NM_199436.2		c.131C>T p.Ser44Leu	missense	Exon 1 of 16	Prot: NP_955468.1 UniProt:

SPAST NM_014946.4

MANE Select

HGVSc / HGVSpc.131C>Tp.Ser44Leu

Exon rankExon 1 of 17

missense

Prot: NP_055761.2

SPAST NM_001363823.2

HGVSc / HGVSpc.131C>Tp.Ser44Leu

Exon rankExon 1 of 17

missense

Prot: NP_001350752.1UniProt: A0A2U3TZR0

SPAST NM_199436.2

HGVSc / HGVSpc.131C>Tp.Ser44Leu

Exon rankExon 1 of 16

missense

Prot: NP_955468.1UniProt: E5KRP6Q9UBP0-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SPAST ENST00000315285.9	TSL:1MANE Select	c.131C>T p.Ser44Leu	missense	Exon 1 of 17	Prot: ENSP00000320885.3 UniProt:
	SPAST ENST00000621856.2	TSL:1	c.131C>T p.Ser44Leu	missense	Exon 1 of 17	Prot: ENSP00000482496.2 UniProt:
	SPAST ENST00000713716.1		c.131C>T p.Ser44Leu	missense	Exon 1 of 18	Prot: ENSP00000519019.1 UniProt:

SPAST ENST00000315285.9

TSL:1MANE Select

HGVSc / HGVSpc.131C>Tp.Ser44Leu

Exon rankExon 1 of 17

missense

Prot: ENSP00000320885.3UniProt: Q9UBP0-1

SPAST ENST00000621856.2

TSL:1

HGVSc / HGVSpc.131C>Tp.Ser44Leu

Exon rankExon 1 of 17

missense

Prot: ENSP00000482496.2UniProt: A0A2U3TZR0

SPAST ENST00000713716.1

HGVSc / HGVSpc.131C>Tp.Ser44Leu

Exon rankExon 1 of 18

missense

Prot: ENSP00000519019.1UniProt: A0AAQ5BGQ0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00500	AC:761	Hom:6	AN:152164	Cov:32
GnomAD2 exomes	AF: 0.00456	AC:1116	Hom:	AN:244870	Cov:
GnomAD4 exome	AF: 0.00815	AC:11895	Hom:65	AN:1459944	Cov:35
GnomAD4 genome	AF: 0.00500	AC:761	Hom:6	AN:152272	Cov:32
TOPMed (Bravo)	AF: 0.00463	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00704	AC:2370	Hom:13	AN:336450	Cov:
Local & regional cohorts 7 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00427	AC:10	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000197	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0167	AC:5	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00654	AC:85	Hom:	AN:13002	Cov:
GenomeAsia100K	AF: 0.00174	AC:6	Hom:	AN:3470	Cov:
Turkish Variome	AF: 0.000923	AC:5	Hom:0	AN:4942	Cov:
UK10K	AF: 0.0110	AC:83	Hom:	AN:7562	Cov:

Showing 13 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00876 *	97	11070	0.00899 *	158	17568
BipEx(Bipolar disorder (including schizoaffective))	0.00943	268	28414	0.00947	273	28840
Epi25(Epilepsy)	0.00663	278	41934	0.00698	467	66882
SCHEMA(Schizophrenia)	0.00443	540	121854	0.00519	991	190806

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign; other; risk factor

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Hereditary spastic paraplegia 4 (8)
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	SPAST-related disorder (1)
-	-	-	Cerebral palsy (1)
-	-	-	SPASTIC PARAPLEGIA 4, MODIFIER OF (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.80	D
GPN-Star LLR	N/A	-5.2
GPN-Star score	N/A	5.2
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.14	D
Mutation Taster	N/A	88/12	polymorphism
MutationAssessor	Benign	0.55	N
PhyloP100	Uncertain	5.1
popEVE	Benign	-3.2
PrimateAI	Pathogenic	0.82	D
PromoterAI	N/A	-0.058	Neutral
PROVEAN	Benign	-1.8	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.15
VESM-3B	Benign	-3.7

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs121908515;

hg19: chr2-32289031;

COSMIC: COSV99043708;

COSMIC: COSV99043708;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar