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…

LOFmechanismARLOEUF 0.941 OMIM phenotype

Clinical Summary— CNNM4

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Gene-Disease Validity (ClinGen)

Jalili syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

50 unique Pathogenic / Likely Pathogenic· 291 VUS of 582 total submissions

Explore recent and relevant literature in Research Assistant →

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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

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCNNM4-related Jalili syndromeLOFAR

This gene — mechanism propensity

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

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

582 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34

Likely Pathogenic16

VUS291

Likely Benign193

Benign22

Conflicting17

Pathogenic

Likely Pathogenic

291

VUS

193

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	27	5	2	0	34
Likely Pathogenic	7	9	0	0	16
VUS	2	251	30	8	291
Likely Benign	0	5	43	145	193
Benign	0	0	16	6	22
Conflicting	—				17
Total	36	270	91	159	573

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 65) ClinVar copy-number / structural variants overlap CNNM4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →