ZNF469

Chr 16AR

zinc finger protein 469

Also known as: BCS, BCS1, Zfp469

NCBI Gene: 84627ENSG00000225614UniProt: Q96JG9

This gene encodes a zinc-finger protein. Low-percent homology to certain collagens suggests that it may function as a transcription factor or extra-nuclear regulator factor for the synthesis or organization of collagen fibers. Mutations in this gene cause brittle cornea syndrome. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Brittle cornea syndrome 1MIM #229200
AR
0
Active trials
29
Pathogenic / LP
691
ClinVar variants
5
Pubs (1 yr)
0.8
Missense Z
0.37
LOEUF
Clinical Summary— ZNF469
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.72) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
29 Pathogenic / Likely Pathogenic· 390 VUS of 691 total submissions
📖
GeneReview available — ZNF469
Authoritative clinical overview · Recommended first read
Open GeneReview ↗
Some data sources returned errors (1)

pubtator: Error: PubTator3 HTTP 502

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.37LOEUF
pLI 0.719
Z-score 4.63
OE 0.20 (0.12–0.37)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
0.77Z-score
OE missense 0.95 (0.92–0.99)
2188 obs / 2292.2 exp
Tolerant

Mild missense constraint

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.0.20 (0.12–0.37)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.95 (0.92–0.99)
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.0.95
0≤1.21.6
LoF obs/exp: 8 / 39.3Missense obs/exp: 2188 / 2292.2Syn Z: 1.38
DN
0.3296th %ile
GOF
0.3491th %ile
LOF
0.70top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 45% of P/LP variants are LoF · LOEUF 0.37

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

ClinVar Variant Classifications

691 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic1
VUS390
Likely Benign267
Benign2
Conflicting3
28
Pathogenic
1
Likely Pathogenic
390
VUS
267
Likely Benign
2
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
0
15
0
28
Likely Pathogenic
0
0
1
0
1
VUS
0
164
225
1
390
Likely Benign
0
12
127
128
267
Benign
0
0
2
0
2
Conflicting
—3
Total13176370129691

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

View in ClinVar →

Protein Context — Lollipop Plot

ZNF469 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ZNF469-related brittle cornea syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients