CNNM4

Chr 2AR

cyclin and CBS domain divalent metal cation transport mediator 4

Also known as: ACDP4, SLC70A4

This gene encodes a metal transporter that functions in sensory neuron activity, biomineralization, and retinal function. Mutations cause Jalili syndrome, characterized by cone-rod dystrophy and amelogenesis imperfecta (defective tooth enamel formation). The condition follows autosomal recessive inheritance.

Summary from RefSeq, OMIM, UniProt
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Primary Disease Associations & Inheritance

Jalili syndromeMIM #217080
AR
0
Active trials
12
Pubs (1 yr)
61
P/LP submissions
19%
P/LP missense
0.94
LOEUF
LOF
Mechanism· G2P
Clinical SummaryCNNM4
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Gene-Disease Validity (ClinGen)
Jalili syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
53 unique Pathogenic / Likely Pathogenic· 196 VUS of 448 total submissions
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GeneReview available — CNNM4
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.94LOEUF
pLI 0.000
Z-score 1.78
OE 0.60 (0.400.94)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
2.37Z-score
OE missense 0.68 (0.620.75)
307 obs / 448.4 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.60 (0.400.94)
00.351.4
Missense OE0.68 (0.620.75)
00.61.4
Synonymous OE1.03
01.21.6
LoF obs/exp: 14 / 23.3Missense obs/exp: 307 / 448.4Syn Z: -0.36
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveCNNM4-related Jalili syndromeLOFAR

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

DN
0.7035th %ile
GOF
0.74top 25%
LOF
0.3164th %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

448 submitted variants in ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic17
VUS196
Likely Benign175
Benign12
Conflicting3
36
Pathogenic
17
Likely Pathogenic
196
VUS
175
Likely Benign
12
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
3
22
0
36
Likely Pathogenic
4
7
6
0
17
VUS
1
162
26
7
196
Likely Benign
0
3
38
134
175
Benign
0
0
7
5
12
Conflicting
3
Total1617599146439

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

View in ClinVar →

Protein Context — Lollipop Plot

CNNM4 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 3 full-text resultsSearch PubTator3 ↗