HAND1

Chr 5

heart and neural crest derivatives expressed 1

Also known as: Hxt, Thing1, bHLHa27, eHand

NCBI Gene: 9421ENSG00000113196UniProt: O96004

The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins, which are asymmetrically expressed in the developing ventricular chambers and play an essential role in cardiac morphogenesis. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries, implicating them as mediators of congenital heart disease. In addition, it has been suggested that this transcription factor may be required for early trophoblast differentiation. [provided by RefSeq, Jul 2008]

196
ClinVar variants
12
Pathogenic / LP
0.11
pLI score
0
Active trials
Clinical Summary— HAND1
🧬
Gene-Disease Validity (ClinGen)
congenital heart disease · ADModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.11) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
12 Pathogenic / Likely Pathogenic· 121 VUS of 196 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.23LOEUF
pLI 0.109
Z-score 1.27
OE 0.39 (0.16–1.23)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.28Z-score
OE missense 1.07 (0.93–1.24)
133 obs / 124.1 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.39 (0.16–1.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.07 (0.93–1.24)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.21
0≤1.21.6
LoF obs/exp: 2 / 5.1Missense obs/exp: 133 / 124.1Syn Z: -1.18

ClinVar Variant Classifications

196 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
VUS121
Likely Benign55
Benign6
Conflicting2
12
Pathogenic
121
VUS
55
Likely Benign
6
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
12
0
12
Likely Pathogenic
0
0
0
0
0
VUS
3
110
8
0
121
Likely Benign
0
4
5
46
55
Benign
0
0
3
3
6
Conflicting
—2
Total31142849196

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

View in ClinVar →

Protein Context — Lollipop Plot

HAND1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
📖
GeneReview available — HAND1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Molecular Mechanisms Regulating Epithelial Mesenchymal Transition (EMT) to Promote Cancer Progression.
Ghafoor S et al.·Int J Mol Sci
2025Review
HAND1 and BARX1 Act as Transcriptional and Anatomic Determinants of Malignancy in Gastrointestinal Stromal Tumor.
Hemming ML et al.·Clin Cancer Res
2021
Human Genetics of Hypoplastic Left Heart Syndrome.
Pfitzer C et al.·Adv Exp Med Biol
2024
Circulating-tumour DNA methylation of HAND1 gene: a promising biomarker in early detection of colorectal cancer.
Shavali M et al.·BMC Med Genomics
2024
Hand1 overexpression inhibits medulloblastoma metastasis.
Asuthkar S et al.·Biochem Biophys Res Commun
2016
RGS2 promotes estradiol biosynthesis by trophoblasts during human pregnancy.
Tang C et al.·Exp Mol Med
2023
[A novel HAND1 mutation associated with sporadic dilated cardiomyopathy].
Xu YJ et al.·Zhonghua Yi Xue Za Zhi
2017
Variation in a Left Ventricle-Specific Hand1 Enhancer Impairs GATA Transcription Factor Binding and Disrupts Conduction System Development and Function.
Vincentz JW et al.·Circ Res
2019
Molecular and cellular role of variants of the promoter region of HAND1 gene in sporadic and isolated ventricular septal defect.
Qi JL et al.·Mol Cell Biochem
2025
[Identification and functional analysis of 
a novel HAND1 mutation associated with congenital ventricular septal defect].
Wang C et al.·Zhong Nan Da Xue Xue Bao Yi Xue Ban
2017Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools