SALL4

Chr 20AD

spalt like transcription factor 4

Also known as: DRRS, HSAL4, IVIC, ZNF797

This gene encodes a zinc finger transcription factor essential for maintaining and renewing embryonic and hematopoietic stem cells. Mutations cause Duane-radial ray syndrome and IVIC syndrome, both presenting with characteristic eye movement abnormalities (Duane anomaly) and limb malformations affecting the radial ray. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variation, indicating critical developmental importance.

Summary from RefSeq, OMIM, UniProt
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Primary Disease Associations & Inheritance

?IVIC syndromeMIM #147750
AD
Duane-radial ray syndromeMIM #607323
AD
1
Active trials
101
Pubs (1 yr)
0
P/LP submissions
P/LP missense
0.10
LOEUF· LoF intol.
LOF
Mechanism· G2P
Clinical SummarySALL4
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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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
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GeneReview available — SALL4
Authoritative clinical overview · Recommended first read
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.10LOEUF
pLI 1.000
Z-score 5.04
OE 0.00 (0.000.10)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
1.08Z-score
OE missense 0.88 (0.820.94)
539 obs / 614.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.00 (0.000.10)
00.351.4
Missense OE0.88 (0.820.94)
00.61.4
Synonymous OE1.18
01.21.6
LoF obs/exp: 0 / 29.5Missense obs/exp: 539 / 614.0Syn Z: -2.39
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveSALL4-related Duane-Radial ray syndromeLOFAD
DN
0.2898th %ile
GOF
0.2398th %ile
LOF
0.85top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function 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 0.10
GOF1 literature citation

Literature Evidence

GOFTypically, SALL4-related Duane-radial ray syndrome is caused by deletions or nonsense mutations; the only missense SALL4 mutation described prior was thought to result in gain of function and produced cranial midline defects.PMID:25823593
LOFHaploinsufficiency for SALL4 due to nonsense or frameshift mutations has been associated with acro-renal ocular syndrome that is characterized by eye defects including Duane anomaly and coloboma, in addition to radial ray malformations and renal abnormalities.PMID:27661448

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

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

SALL4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Literature
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