FLNA

Chr XX-linkedXLRXLD

filamin A

Also known as: ABP-280, ABPX, CSBS, CVD1, FGS2, FLN, FLN-A, FLN1

NCBI Gene: 2316 ENSG00000196924 UniProt: P21333

The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

Primary Disease Associations & Inheritance

?FG syndrome 2MIM #300321

X-linked

Cardiac valvular dysplasia, X-linkedMIM #314400

X-linked

Congenital short bowel syndromeMIM #300048

XLR

Frontometaphyseal dysplasia 1MIM #305620

XLR

Heterotopia, periventricular, 1MIM #300049

XLD

Intestinal pseudoobstruction, neuronalMIM #300048

XLR

Melnick-Needles syndromeMIM #309350

XLD

Otopalatodigital syndrome, type IMIM #311300

XLD

Otopalatodigital syndrome, type IIMIM #304120

XLD

Terminal osseous dysplasiaMIM #300244

XLD

UniProtPeriventricular nodular heterotopia 1

363

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— FLNA

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Gene-Disease Validity (ClinGen)

periventricular nodular heterotopia · XLDefinitive

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 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

25 Pathogenic / Likely Pathogenic· 172 VUS of 363 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.08LOEUF

pLI 1.000

Z-score 7.89

OE 0.03 (0.01–0.08)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

3.78Z-score

OE missense 0.70 (0.66–0.74)

867 obs / 1241.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.03 (0.01–0.08)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.66–0.74)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.16

0≤1.21.6

LoF obs/exp: 2 / 76.5Missense obs/exp: 867 / 1241.9Syn Z: -2.98

ClinVar Variant Classifications

363 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18

Likely Pathogenic7

VUS172

Likely Benign149

Benign15

Conflicting2

Pathogenic

Likely Pathogenic

172

VUS

149

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	0	9	0	18
Likely Pathogenic	6	1	0	0	7
VUS	2	155	11	4	172
Likely Benign	0	12	68	69	149
Benign	0	9	1	5	15
Conflicting	—				2
Total	17	177	89	78	363

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

View in ClinVar →

Protein Context — Lollipop Plot

FLNA · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

FLNA-related epileptic encephalopathy

definitive

Monoallelic X HeterozygousUndeterminedAltered Gene Product Structure

Dev. DisordersSkin

G2P ↗

missense variantinframe deletioninframe insertion

FLNA-related otopalatodigital syndrome

definitive

Monoallelic X HemizygousUndeterminedAltered Gene Product Structure

Dev. DisordersSkin

G2P ↗

missense variantinframe deletioninframe insertion

FLNA-related frontometaphyseal dysplasia

definitive

Monoallelic X HemizygousGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkeletal

G2P ↗

FLNA-related Melnick-Needles syndrome

definitive

Monoallelic X HeterozygousUndeterminedUncertain

Dev. DisordersSkinSkeletal

G2P ↗

FLNA-related terminal osseous dysplasia

definitive

Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product

Dev. DisordersSkinSkeletal

G2P ↗

FLNA-related periventricular nodular heterotopia

definitive

Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product

Dev. DisordersSkin

G2P ↗

FLNA-related congenital idiopathic intestinal pseudoobstruction

definitive

Monoallelic X HemizygousUndeterminedIncreased Gene Product Level

Dev. Disorders

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

FILAMIN A; FLNA

MIM #300017 · *

?FG syndrome 2

MIM #300321