HYCC1

Chr 7AR

hyccin PI4KA lipid kinase complex subunit 1

Also known as: DRCTNNB1A, FAM126A, HCC, HLD5

NCBI Gene: 84668 ENSG00000122591 UniProt: Q9BYI3 OMIM: 610531

The protein is a component of a complex that localizes phosphatidylinositol 4-kinase to the plasma membrane and regulates phosphatidylinositol 4-phosphate synthesis, playing a key role in oligodendrocyte formation and myelination of the central and peripheral nervous systems. Mutations cause leukodystrophy, hypomyelinating, 5 (also known as hypomyelination with congenital cataract), which follows autosomal recessive inheritance. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.485), and the congenital onset is reflected in the phenotype name.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene may play a part in the beta-catenin/Lef signaling pathway. Expression of this gene is down-regulated by beta-catenin. Defects in this gene are a cause of hypomyelination with congenital cataract (HCC). [provided by RefSeq, Oct 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.481 OMIM phenotype

Clinical Summary— HYCC1

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Gene-Disease Validity (ClinGen)

hypomyelinating leukodystrophy 5 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

21 unique Pathogenic / Likely Pathogenic· 190 VUS of 396 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HYCC1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.121

Z-score 3.58

OE 0.26 (0.15–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.98Z-score

OE missense 0.83 (0.74–0.93)

224 obs / 269.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.15–0.48)

0≤0.351.4

Missense OE?0.83 (0.74–0.93)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 7 / 27.1Missense obs/exp: 224 / 269.3Syn Z: -1.41

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHYCC1-related leukodystrophy, hypomyelinatingLOFAR

This gene — mechanism propensity

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

0.6649th %ile

GOF

0.6930th %ile

LOF

0.4628th %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

396 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic14

VUS190

Likely Benign121

Benign40

Conflicting13

Pathogenic

Likely Pathogenic

190

VUS

121

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	1	0	0	7
Likely Pathogenic	14	0	0	0	14
VUS	3	119	64	4	190
Likely Benign	0	11	43	67	121
Benign	0	1	35	4	40
Conflicting	—				13
Total	23	132	142	75	385

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap HYCC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →