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 nuclear body and pericentric heterochromatin. Part of transcription regulator complex. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.35

LOEUF

—

Mechanism

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

Background carrier burden — how many people carry a rare variant somewhere in FLYWCH1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 19

1,681 rare PASS variants

Rare truncating (LoF)

1 in 260

242 rare PASS variants

Rare synonymous (reference)

1 in 35

722 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FLYWCH1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 28	1 in 380
South Asian	~43k	1 in 17	1 in 170
Remaining (unassigned)	~30k	1 in 18	1 in 130
European (Finnish)	~27k	1 in 53	1 in 260
Admixed American	~22k	1 in 16	1 in 280
African / African American	~21k	1 in 19	1 in 330
East Asian	~20k	1 in 22	1 in 250
Ashkenazi Jewish	~13k	1 in 78	1 in 460
Middle Eastern	~2,884	1 in 18	1 in 570

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 8 coding exons well covered in gnomAD exomes; exon 9 marginal. Genomes: 7 of 8 (exon 7 below).? see exons ↓