FLYWCH1

Chr 16

FLYWCH-type zinc finger 1

NCBI Gene: 84256 ENSG00000059122 UniProt: Q4VC44 OMIM: 620431

FLYWCH1 encodes a transcription cofactor that negatively regulates gene transcription and participates in DNA damage response signaling. Mutations cause autosomal dominant neurodevelopmental disorder with developmental delay, seizures, and behavioral abnormalities. The gene is extremely intolerant to loss-of-function variants (pLI ~1.0), indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

Enables transcription coactivator binding activity and transcription corepressor activity. Involved in DNA damage response and negative regulation of transcription by RNA polymerase II. Located in cytosol; nuclear body; and pericentric heterochromatin. Part of transcription regulator complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOEUF 1.35

Clinical Summary— FLYWCH1

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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

208 VUS of 257 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?

1.35LOEUF

pLI 0.000

Z-score 0.08

OE 0.98 (0.73–1.35)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.61Z-score

OE missense 1.35 (1.26–1.44)

606 obs / 450.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.98 (0.73–1.35)

0≤0.351.4

Missense OE?1.35 (1.26–1.44)

0≤0.61.4

Synonymous OE?1.48

0≤1.21.6

LoF obs/exp: 28 / 28.4Missense obs/exp: 606 / 450.0Syn Z: -5.20

ClinVar Variant Classifications

257 submitted variants in ClinVar

ClinVar

Classification Summary

VUS208

Likely Benign19

Benign4

208

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	208	0	208
Likely Benign	13	6	19
Benign	2	2	4
Total	223	8	231

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 51) ClinVar copy-number / structural variants overlap FLYWCH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →