CNNM4

Chr 2AR

cyclin and CBS domain divalent metal cation transport mediator 4

Also known as: ACDP4, SLC70A4

NCBI Gene: 26504 ENSG00000158158 UniProt: Q6P4Q7 OMIM: 607805

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play a role in metal ion transport. Mutations in this gene are associated with Jalili syndrome which consists of cone-rod dystrophy and amelogenesis imperfecta. [provided by RefSeq, Feb 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Jalili syndromeMIM #217080

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Jalili syndrome · AR · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.94

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — CNNM4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.78

OE 0.60 (0.40–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.37Z-score

OE missense 0.68 (0.62–0.75)

307 obs / 448.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.60 (0.40–0.94)

0≤0.351.4

Missense OE?0.68 (0.62–0.75)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 14 / 23.3Missense obs/exp: 307 / 448.4Syn Z: -0.36

Background carrier burden — how many people carry a rare variant somewhere in CNNM4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 90

857 rare PASS variants

Rare truncating (LoF)

1 in 2,400

92 rare PASS variants

Rare synonymous (reference)

1 in 100

439 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CNNM4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 2,000
South Asian	~43k	1 in 77	1 in 2,900
Remaining (unassigned)	~30k	1 in 81	1 in 2,300
European (Finnish)	~27k	1 in 410	≈ 1 in 8,900
Admixed American	~22k	1 in 88	1 in 2,000
African / African American	~21k	1 in 92	≈ 1 in 4,200
East Asian	~20k	1 in 120	1 in 2,800
Ashkenazi Jewish	~13k	1 in 300	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 120	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓