HESX1

Chr 3ADAR

HESX homeobox 1

Also known as: ANF, CPHD5, RPX

NCBI Gene: 8820 ENSG00000163666 UniProt: Q9UBX0 OMIM: 601802

This gene encodes a conserved homeobox protein that is a transcriptional repressor in the developing forebrain and pituitary gland. Mutations in this gene are associated with septooptic dysplasia, HESX1-related growth hormone deficiency, and combined pituitary hormone deficiency. [provided by RefSeq, Jul 2008]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 1.243 OMIM phenotypes

Clinical Summary— HESX1

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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

22 unique Pathogenic / Likely Pathogenic· 73 VUS of 140 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HESX1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.24LOEUF

pLI 0.001

Z-score 1.07

OE 0.63 (0.34–1.24)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.16Z-score

OE missense 1.05 (0.89–1.24)

99 obs / 94.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.63 (0.34–1.24)

0≤0.351.4

Missense OE?1.05 (0.89–1.24)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 6 / 9.6Missense obs/exp: 99 / 94.7Syn Z: 0.68

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongHESX1-related septooptic dysplasiaLOFAR

strongHESX1-related combined pituitary hormone deficiencyLOFAD

This gene — mechanism propensity

0.75top 25%

GOF

0.6150th %ile

LOF

0.3843th %ile

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

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNThis dominant negative activity of HESX1(R160C) is mediated by the Hesx1 repression domain, supporting the idea that the repression domain is implicated in interactions between homeodomain proteins. Our data suggest a possible molecular paradigm for the dominant inheritance observed in some pituitar1

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

References

1.PMID 11748154 ↗

ClinVar Variant Classifications

140 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic8

VUS73

Likely Benign24

Benign5

Conflicting13

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	2	0	0	14
Likely Pathogenic	8	0	0	0	8
VUS	2	63	8	0	73
Likely Benign	0	1	10	13	24
Benign	0	0	5	0	5
Conflicting	—				13
Total	22	66	23	13	137

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap HESX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →