AUTS2

Chr 7AD

activator of transcription and developmental regulator AUTS2

Also known as: FBRSL2, MRD26

NCBI Gene: 26053 ENSG00000158321 UniProt: Q8WXX7 OMIM: 607270

The AUTS2 protein localizes to the nucleus and functions in neurodevelopment. Mutations cause intellectual developmental disorder through a loss-of-function mechanism, with autosomal dominant inheritance. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene has been implicated in neurodevelopment and as a candidate gene for numerous neurological disorders, including autism spectrum disorders, intellectual disability, and developmental delay. Mutations in this gene have also been associated with non-neurological disorders, such as acute lymphoblastic leukemia, aging of the skin, early-onset androgenetic alopecia, and certain cancers. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.251 OMIM phenotype

Clinical Summary— AUTS2

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

119 unique Pathogenic / Likely Pathogenic· 574 VUS of 1333 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — AUTS2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.25LOEUF

pLI 0.999

Z-score 5.78

OE 0.13 (0.08–0.25)

Highly constrained

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

Missense Constraint?

2.22Z-score

OE missense 0.78 (0.73–0.83)

617 obs / 793.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.13 (0.08–0.25)

0≤0.351.4

Missense OE?0.78 (0.73–0.83)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 7 / 52.0Missense obs/exp: 617 / 793.3Syn Z: -1.17

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveAUTS2-related syndromic intellectual disabilityLOFAD

This gene — mechanism propensity

0.2898th %ile

GOF

0.15100th %ile

LOF

0.90top 5%

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

LOFprediction above median · 1 literature citation · 73% of P/LP variants are LoF · LOEUF 0.25 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFHaploinsufficiency of AUTS2 has been associated with neurodevelopmental disorders and dysmorphic features (MIM # 615834).1

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

References

1.PMID 33577136 ↗

ClinVar Variant Classifications

1333 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic71

Likely Pathogenic48

VUS574

Likely Benign407

Benign146

Conflicting70

Pathogenic

Likely Pathogenic

574

VUS

407

Likely Benign

146

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	53	6	12	0	71
Likely Pathogenic	34	13	1	0	48
VUS	18	512	38	6	574
Likely Benign	1	82	98	226	407
Benign	0	39	88	19	146
Conflicting	—				70
Total	106	652	237	251	1,316

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

View in ClinVar →

71 pathogenic / likely-pathogenic (of 108) ClinVar copy-number / structural variants overlap AUTS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →