SMYD4

Chr 17

SET and MYND domain containing 4

Also known as: ZMYND21

NCBI Gene: 114826 ENSG00000186532 UniProt: Q8IYR2 OMIM: 619134

The SMYD4 protein is a lysine methyltransferase that regulates gene expression during cardiac development by methylating target proteins and modulating histone deacetylase activity. Mutations cause autosomal recessive developmental disorders primarily affecting the heart. This gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable histone deacetylase binding activity. Involved in heart development. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOEUF 1.08

Clinical Summary— SMYD4

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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

1 unique Pathogenic / Likely Pathogenic· 125 VUS of 161 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?

1.08LOEUF

pLI 0.000

Z-score 1.21

OE 0.78 (0.57–1.08)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.01Z-score

OE missense 1.00 (0.93–1.08)

462 obs / 461.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.78 (0.57–1.08)

0≤0.351.4

Missense OE?1.00 (0.93–1.08)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 26 / 33.5Missense obs/exp: 462 / 461.5Syn Z: 0.23

ClinVar Variant Classifications

161 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS125

Likely Benign18

Benign1

Conflicting1

Pathogenic

125

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	0	0	0	0	0
VUS	0	125	0	0	125
Likely Benign	0	18	0	0	18
Benign	0	1	0	0	1
Conflicting	—				1
Total	0	144	1	0	146

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

View in ClinVar →

76 pathogenic / likely-pathogenic (of 96) ClinVar copy-number / structural variants overlap SMYD4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →