SH3PXD2B

Chr 5AR

SH3 and PX domains 2B

Also known as: FAD49, FTHS, HOFI, KIAA1295, TKS4, TSK4

NCBI Gene: 285590 ENSG00000174705 UniProt: A1X283 OMIM: 613293

This adapter protein is essential for podosome formation and extracellular matrix degradation, binding matrix metalloproteinases and NADPH oxidases to organize reactive oxygen species generation. Biallelic mutations cause Frank-ter Haar syndrome, a rare autosomal recessive disorder affecting skeletal, cardiac, and other systems. The gene is highly constrained against loss-of-function variation (LOEUF 0.488), reflecting its critical cellular functions.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an adapter protein that is characterized by a PX domain and four Src homology 3 domains. The encoded protein is required for podosome formation and is involved in cell adhesion and migration of numerous cell types. Mutations in this gene are the cause of Frank-ter Haar syndrome (FTHS), and also Borrone Dermato-Cardio-Skeletal (BDCS) syndrome. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.491 OMIM phenotype

Clinical Summary— SH3PXD2B

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Gene-Disease Validity (ClinGen)

Frank-Ter Haar syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

18 unique Pathogenic / Likely Pathogenic· 322 VUS of 681 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.49LOEUF

pLI 0.004

Z-score 4.08

OE 0.30 (0.19–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.53Z-score

OE missense 0.94 (0.87–1.01)

511 obs / 545.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.19–0.49)

0≤0.351.4

Missense OE?0.94 (0.87–1.01)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 12 / 39.8Missense obs/exp: 511 / 545.6Syn Z: 0.83

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSH3PXD2B-related Frank-ter Haar syndromeLOFAR

This gene — mechanism propensity

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

0.7131th %ile

GOF

0.6247th %ile

LOF

0.3940th %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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

681 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic8

VUS322

Likely Benign195

Benign85

Conflicting49

Pathogenic

Likely Pathogenic

322

VUS

195

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	0	2	0	10
Likely Pathogenic	7	1	0	0	8
VUS	10	230	81	1	322
Likely Benign	0	16	78	101	195
Benign	0	6	71	8	85
Conflicting	—				49
Total	25	253	232	110	669

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap SH3PXD2B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →