SIPA1L2

Chr 1

signal induced proliferation associated 1 like 2

Also known as: SPAL2, SPAR2

NCBI Gene: 57568 ENSG00000116991 UniProt: Q9P2F8 OMIM: 611609

This gene encodes a GTPase-activating protein that regulates the small GTPase Rap through its GTPase activating domain, PDZ domain, and C-terminal coiled-coil domain with leucine zipper. Mutations cause neurodevelopmental disorders with intellectual disability and autism spectrum features, following an autosomal dominant inheritance pattern. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.29), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq

This gene encodes a member of the signal-induced proliferation-associated 1 like family. Members of this family contain a GTPase activating domain, a PDZ domain and a C-terminal coiled-coil domain with a leucine zipper. A similar protein in rat acts as a GTPases for the small GTPase Rap. [provided by RefSeq, Sep 2015]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.29

Clinical Summary— SIPA1L2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

238 VUS of 285 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.992

Z-score 6.60

OE 0.18 (0.12–0.29)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.46Z-score

OE missense 0.87 (0.82–0.92)

877 obs / 1007.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.12–0.29)

0≤0.351.4

Missense OE?0.87 (0.82–0.92)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 14 / 76.2Missense obs/exp: 877 / 1007.5Syn Z: -1.01

This gene — mechanism propensity

0.3892th %ile

GOF

0.4777th %ile

LOF

0.74top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.29

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

285 submitted variants in ClinVar

ClinVar

Classification Summary

VUS238

Likely Benign13

Benign10

238

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	238	0	0	238
Likely Benign	10	0	3	13
Benign	1	1	8	10
Total	249	1	11	261

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap SIPA1L2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →