SALL1

Chr 16AD

spalt like transcription factor 1

Also known as: HEL-S-89, HSAL1, Sal-1, TBS, ZNF794

NCBI Gene: 6299 ENSG00000103449 UniProt: Q9NSC2 OMIM: 602218

This gene encodes a zinc finger transcriptional repressor that plays an essential role in organogenesis, particularly ureteric bud invasion during kidney development. Mutations cause Townes-Brocks syndrome, which affects the kidneys, ears, and other organ systems, with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.20), indicating that most pathogenic variants are likely missense changes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.202 OMIM phenotypes

Clinical Summary— SALL1

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Gene-Disease Validity (ClinGen)

Townes-Brocks syndrome 1 · 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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.20LOEUF

pLI 1.000

Z-score 4.92

OE 0.06 (0.02–0.20)

Highly constrained

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

Missense Constraint

0.72Z-score

OE missense 0.93 (0.87–0.99)

687 obs / 742.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.06 (0.02–0.20)

0≤0.351.4

Missense OE0.93 (0.87–0.99)

0≤0.61.4

Synonymous OE1.04

0≤1.21.6

LoF obs/exp: 2 / 32.1Missense obs/exp: 687 / 742.3Syn Z: -0.50

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSALL1-related Townes-Brocks syndromeLOFAD

0.3395th %ile

GOF

0.2397th %ile

LOF

0.83top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.20

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNOver 60 nonsense and frameshift mutations have been identified in SALL1, the zinc finger transcription factor causing TBS, and are proposed to cause disease via a dominant negative mechanism.PMID:22308078

GOFSince the mutations that cause TBS could express a truncated SALL1 protein containing the domain necessary for transcriptional repression but lacking the complete DNA binding domain, we hypothesized that TBS is due to dominant-negative or gain-of-function activity of a mutant protein.PMID:12915476

LOFTruncating mutations of SALL1 have been shown to cause Townes-Brocks syndrome and are thought to result in SALL1 haploinsufficiency.PMID:10610715

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