RCHY1

Chr 4

ring finger and CHY zinc finger domain containing 1

Also known as: ARNIP, CHIMP, PIRH2, PRO1996, RNF199, ZCHY, ZNF363

NCBI Gene: 25898 ENSG00000163743 UniProt: Q96PM5 OMIM: 607680

The protein functions as an E3 ubiquitin ligase that mediates ubiquitination and proteasomal degradation of multiple target proteins including p53, TP73, and HDAC1, and is involved in ribosome-associated quality control pathways. Mutations in RCHY1 cause autosomal recessive intellectual disability with microcephaly, seizures, and spasticity with onset in infancy or early childhood. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.636), consistent with its autosomal recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene has ubiquitin ligase activity. It mediates E3-dependent ubiquitination and proteasomal degradation of target proteins, including tumor protein 53, histone deacetylase 1, and cyclin-dependent kinase inhibitor 1B, thus regulating their levels and cell cycle progression. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jun 2013]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.64

Clinical Summary— RCHY1

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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

1 unique Pathogenic / Likely Pathogenic· 20 VUS of 41 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.066

Z-score 2.63

OE 0.30 (0.16–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.20Z-score

OE missense 0.71 (0.61–0.84)

101 obs / 141.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.16–0.64)

0≤0.351.4

Missense OE?0.71 (0.61–0.84)

0≤0.61.4

Synonymous OE?0.80

0≤1.21.6

LoF obs/exp: 5 / 16.5Missense obs/exp: 101 / 141.3Syn Z: 1.04

This gene — mechanism propensity

0.5181th %ile

GOF

0.6833th %ile

LOF

0.3259th %ile

The highest-scoring mechanism for this gene is gain-of-function.

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

41 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS20

Likely Benign5

Benign1

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	1	0	1
Likely Pathogenic	0	0	0
VUS	20	0	20
Likely Benign	3	2	5
Benign	0	1	1
Total	24	3	27

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap RCHY1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →