HAPLN3

Chr 15

hyaluronan and proteoglycan link protein 3

Also known as: EXLD1, HsT19883

NCBI Gene: 145864 ENSG00000140511 UniProt: Q96S86

The protein encoded by this gene binds hyaluronic acid and may function in cell adhesion as part of the hyaluronan and proteoglycan link protein family. Mutations cause autosomal recessive neurodevelopmental disorder with progressive microcephaly, seizures, and brain atrophy. The gene shows minimal constraint against loss-of-function variants, with neurological symptoms typically manifesting in early childhood.

ResearchSummary from RefSeq, UniProt

This gene belongs to the hyaluronan and proteoglycan binding link protein gene family. The protein encoded by this gene may function in hyaluronic acid binding and cell adhesion. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.24

Clinical Summary— HAPLN3

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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

98 VUS of 115 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?

1.24LOEUF

pLI 0.000

Z-score 0.89

OE 0.75 (0.47–1.24)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.22Z-score

OE missense 0.96 (0.86–1.07)

243 obs / 253.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.75 (0.47–1.24)

0≤0.351.4

Missense OE?0.96 (0.86–1.07)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 11 / 14.7Missense obs/exp: 243 / 253.0Syn Z: -0.08

This gene — mechanism propensity

0.6842th %ile

GOF

0.6345th %ile

LOF

0.2873th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

115 submitted variants in ClinVar

ClinVar

Classification Summary

VUS98

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	98	98
Likely Benign	4	4
Benign	0	0
Total	102	102

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap HAPLN3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →