HAX1

Chr 1AR

HCLS1 associated protein X-1

Also known as: HCLSBP1, HS1BP1, SCN3

NCBI Gene: 10456 ENSG00000143575 UniProt: O00165 OMIM: 605998

The HAX1 protein recruits the Arp2/3 complex to regulate cortical actin cytoskeleton reorganization and is involved in clathrin-mediated endocytosis. Mutations cause autosomal recessive severe congenital neutropenia (Kostmann disease), a primary immunodeficiency affecting neutrophil production and function. The gene shows extremely low tolerance to loss-of-function variants (pLI near 1), indicating it is highly constrained and essential for normal cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is known to associate with hematopoietic cell-specific Lyn substrate 1, a substrate of Src family tyrosine kinases. It also interacts with the product of the polycystic kidney disease 2 gene, mutations in which are associated with autosomal-dominant polycystic kidney disease, and with the F-actin-binding protein, cortactin. It was earlier thought that this gene product is mainly localized in the mitochondria, however, recent studies indicate it to be localized in the cell body. Mutations in this gene result in autosomal recessive severe congenital neutropenia, also known as Kostmann disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.381 OMIM phenotype

Clinical Summary— HAX1

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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

65 unique Pathogenic / Likely Pathogenic· 329 VUS of 691 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.38LOEUF

pLI 0.000

Z-score 0.52

OE 0.85 (0.54–1.38)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.14Z-score

OE missense 0.97 (0.85–1.11)

158 obs / 162.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.85 (0.54–1.38)

0≤0.351.4

Missense OE?0.97 (0.85–1.11)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 12 / 14.1Missense obs/exp: 158 / 162.9Syn Z: 0.79

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHAX1-related neutropenia, severe congenitalLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6840th %ile

GOF

0.4381th %ile

LOF

0.3842th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

691 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33

Likely Pathogenic32

VUS329

Likely Benign272

Benign6

Conflicting12

Pathogenic

Likely Pathogenic

329

VUS

272

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	33	0	0	0	33
Likely Pathogenic	30	0	2	0	32
VUS	2	312	12	3	329
Likely Benign	0	14	91	167	272
Benign	0	0	6	0	6
Conflicting	—				12
Total	65	326	111	170	684

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap HAX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →