DIAPH1

Chr 5ADAR

diaphanous related formin 1

Also known as: DFNA1, DIA1, DRF1, LFHL1, SCBMS, hDIA1, mDia1

NCBI Gene: 1729 ENSG00000131504 UniProt: O60610 OMIM: 602121

DIAPH1 encodes a formin protein that nucleates and elongates actin filaments, particularly in hair cells of the inner ear, and also regulates microtubule stabilization and cell shape. Mutations cause autosomal dominant progressive low-frequency sensorineural hearing loss (often with thrombocytopenia) and autosomal recessive seizures with cortical blindness and microcephaly syndrome. The gene is highly constrained against loss-of-function variants (pLI 0.92, LOEUF 0.32), reflecting its essential cellular functions.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.322 OMIM phenotypes

Clinical Summary— DIAPH1

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Gene-Disease Validity (ClinGen)

DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

64 unique Pathogenic / Likely Pathogenic· 975 VUS of 1898 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DIAPH1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.915

Z-score 5.80

OE 0.20 (0.13–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.65Z-score

OE missense 0.82 (0.76–0.88)

535 obs / 653.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.20 (0.13–0.32)

0≤0.351.4

Missense OE?0.82 (0.76–0.88)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 12 / 60.8Missense obs/exp: 535 / 653.8Syn Z: -0.65

This gene — mechanism propensity

0.4388th %ile

GOF

0.5367th %ile

LOF

0.56top 25%

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

LOF92% of P/LP variants are LoF · LOEUF 0.32

GOF1 literature citation

Literature Evidence

GOFHere, we report the first cases of DIAPH1-related disorder in Australia caused by the autosomal dominant gain-of-function DIAPH1 R1213X variant formed by truncation of the protein within the diaphanous auto-regulatory domain (DAD) with loss of regulatory motifs responsible for autoinhibitory interac1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 34223798 ↗

ClinVar Variant Classifications

1898 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36

Likely Pathogenic28

VUS975

Likely Benign723

Benign46

Conflicting59

Pathogenic

Likely Pathogenic

975

VUS

723

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	34	0	2	0	36
Likely Pathogenic	25	2	1	0	28
VUS	9	852	92	22	975
Likely Benign	1	20	361	341	723
Benign	0	3	40	3	46
Conflicting	—				59
Total	69	877	496	366	1,867

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap DIAPH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →