HOXD1

Chr 2

homeobox D1

Also known as: HOX4, HOX4G, Hox-4.7

NCBI Gene: 3231 ENSG00000128645 UniProt: Q9GZZ0 OMIM: 142987

This gene is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. This nuclear protein functions as a sequence-specific transcription factor that is involved in differentiation and limb development. Mutations in this gene have been associated with severe developmental defects on the anterior-posterior (a-p) limb axis. [provided by RefSeq, Jul 2008]

OMIM Research

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.21

Clinical Summary— HOXD1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

46 VUS of 49 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.21LOEUF

pLI 0.003

Z-score 1.16

OE 0.57 (0.30–1.21)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.04Z-score

OE missense 1.01 (0.89–1.14)

173 obs / 171.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.57 (0.30–1.21)

0≤0.351.4

Missense OE?1.01 (0.89–1.14)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 5 / 8.7Missense obs/exp: 173 / 171.7Syn Z: 0.13

This gene — mechanism propensity

0.74top 25%

GOF

0.5758th %ile

LOF

0.4627th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

49 submitted variants in ClinVar

ClinVar

Classification Summary

VUS46

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	1	45	46
Likely Benign	0	1	1
Benign	0	0	0
Total	1	46	47

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap HOXD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →