SPG21

Chr 15AR

SPG21 abhydrolase domain containing, maspardin

Also known as: ABHD21, ACP33, BM-019, GL010, MAST

NCBI Gene: 51324 ENSG00000090487 UniProt: Q9NZD8 OMIM: 604360

The protein binds to CD4 and modulates T cell activation by interacting with CD4's hydrophobic C-terminal amino acids through its noncatalytic alpha/beta hydrolase fold domain. Mutations cause autosomal recessive spastic paraplegia 21 (also known as Mast syndrome), which involves spasticity and neurodegeneration primarily affecting the lower extremities. This gene shows low constraint against loss-of-function variants (pLI 0.0007), consistent with its autosomal recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene binds to the hydrophobic C-terminal amino acids of CD4 which are involved in repression of T cell activation. The interaction with CD4 is mediated by the noncatalytic alpha/beta hydrolase fold domain of this protein. It is thus proposed that this gene product modulates the stimulatory activity of CD4. Mutations in this gene are associated with autosomal recessive spastic paraplegia 21 (SPG21), also known as mast syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

ARLOEUF 0.833 OMIM phenotypes

Clinical Summary— SPG21

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 76 VUS of 205 total submissions

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GeneReview available — SPG21

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.001

Z-score 2.07

OE 0.46 (0.27–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.16Z-score

OE missense 0.75 (0.65–0.87)

127 obs / 169.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.46 (0.27–0.83)

0≤0.351.4

Missense OE?0.75 (0.65–0.87)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 8 / 17.3Missense obs/exp: 127 / 169.4Syn Z: -0.51

ClinVar Variant Classifications

205 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic8

VUS76

Likely Benign58

Benign25

Conflicting13

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	1	0	0	6
Likely Pathogenic	7	0	1	0	8
VUS	1	52	19	4	76
Likely Benign	0	0	31	27	58
Benign	0	0	25	0	25
Conflicting	—				13
Total	13	53	76	31	186

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

10 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap SPG21 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →