FZD6

Chr 8AR

frizzled class receptor 6

Also known as: FZ-6, FZ6, HFZ6, NDNC1, NDNC10

NCBI Gene: 8323 ENSG00000164930 UniProt: O60353 OMIM: 603409

This gene encodes a 7-transmembrane receptor for Wnt signaling proteins that regulates canonical Wnt/beta-catenin signaling and planar cell polarity, particularly in inner ear sensory cells and during neural tube closure. Autosomal recessive mutations cause nonsyndromic congenital nail disorder, with the gene showing low constraint to loss-of-function variation. The phenotype appears to be congenital and primarily affects nail development without other syndromic features.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene represents a member of the 'frizzled' gene family, which encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The protein encoded by this family member contains a signal peptide, a cysteine-rich domain in the N-terminal extracellular region, and seven transmembrane domains, but unlike other family members, this protein does not contain a C-terminal PDZ domain-binding motif. This protein functions as a negative regulator of the canonical Wnt/beta-catenin signaling cascade, thereby inhibiting the processes that trigger oncogenic transformation, cell proliferation, and inhibition of apoptosis. Alternative splicing results in multiple transcript variants, some of which do not encode a protein with a predicted signal peptide.[provided by RefSeq, Aug 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.081 OMIM phenotype

Clinical Summary— FZD6

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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

7 unique Pathogenic / Likely Pathogenic· 83 VUS of 111 total submissions

Explore recent and relevant literature in Research Assistant →

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 1.22

OE 0.76 (0.54–1.08)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.40Z-score

OE missense 0.80 (0.72–0.88)

297 obs / 373.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.54–1.08)

0≤0.351.4

Missense OE?0.80 (0.72–0.88)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 22 / 29.1Missense obs/exp: 297 / 373.0Syn Z: 0.61

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFZD6-related nail disorder non-syndromic congenitalLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6937th %ile

GOF

0.75top 25%

LOF

0.3259th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

111 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic1

VUS83

Likely Benign9

Benign3

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	2	0	0	6
Likely Pathogenic	1	0	0	0	1
VUS	0	82	1	0	83
Likely Benign	0	4	1	4	9
Benign	0	1	1	1	3
Conflicting	—				1
Total	5	89	3	5	103

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

View in ClinVar →

39 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap FZD6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →