LY6H

Chr 8

lymphocyte antigen 6 family member H

Also known as: NMLY6

NCBI Gene: 4062 ENSG00000176956 UniProt: O94772 OMIM: 603625

The LY6H protein modulates nicotinic acetylcholine receptor activity by inhibiting alpha-3:beta-4-containing receptors and affecting intracellular trafficking of alpha-7-containing receptors. Currently, no human diseases have been definitively associated with LY6H mutations in the medical literature. The gene shows tolerance to loss-of-function variants with a low constraint score (pLI = 0.17, LOEUF = 1.0).

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable acetylcholine receptor binding activity and acetylcholine receptor inhibitor activity. Predicted to be involved in acetylcholine receptor signaling pathway. Predicted to be located in extracellular region. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.00

Clinical Summary— LY6H

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

24 VUS of 26 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?

1.00LOEUF

pLI 0.168

Z-score 1.58

OE 0.32 (0.13–1.00)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.61Z-score

OE missense 0.81 (0.67–1.00)

67 obs / 82.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.13–1.00)

0≤0.351.4

Missense OE?0.81 (0.67–1.00)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 2 / 6.3Missense obs/exp: 67 / 82.5Syn Z: -0.18

This gene — mechanism propensity

0.6358th %ile

GOF

0.6540th %ile

LOF

0.2774th %ile

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

GOFprediction above median

DNprediction 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

26 submitted variants in ClinVar

ClinVar

Classification Summary

VUS24

Likely Benign1

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	24	24
Likely Benign	1	1
Benign	0	0
Total	25	25

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

View in ClinVar →

58 pathogenic / likely-pathogenic (of 66) ClinVar copy-number / structural variants overlap LY6H — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →