# NM_017649.5(CNNM2):c.2175G>C (p.Leu725Phe)

https://sugi.bio/variant/cnnm2-p-leu725phe

## Summary

**CNNM2 p.Leu725Phe (c.2175G>C)** is classified **Uncertain significance** in CNNM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-08). AlphaMissense: likely benign (0.2296); Very rare (popmax 0.0011%, sas); Associated with hypomagnesemia, seizures, and intellectual disability 1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CNNM2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to hypomagnesemia, seizures, and intellectual disability 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025248/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CNNM2](https://sugi.bio/atlas/gene/CNNM2/) |
| Protein change (HGVS p.) | p.Leu725Phe |
| Coding change (HGVS c.) | c.2175G>C |
| MANE Select transcript | [NM_017649](https://www.ncbi.nlm.nih.gov/nuccore/NM_017649) |
| Variant type | single nucleotide variant |
| Location | chr10:103071781-103071781 (GRCh38) |
| ClinVar | [VCV3590489](https://www.ncbi.nlm.nih.gov/clinvar/variation/3590489/) |

**All HGVS expressions:** `NC_000010.10:g.104831538G>C`, `NC_000010.11:g.103071781G>C`, `NG_031932.1:g.158464G>C`, `NG_031932.2:g.158489G>C`, `NM_017649.5:c.2175G>C`, `NM_199076.3:c.2167+3059G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2296)
- REVEL 0.236 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.918 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 11.904, GERP 2.35, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.8**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.85** across the covering region of the MANE Select transcript (103,068,652–103,077,177), spanning 8,525 bp. Chi-square p 0.026. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.20 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,068 in the highest group · 3/1,461,608 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00156% | 63,968 |
| South Asian (grpmax) | 0.0011% | 91,068 |
| European (non-Finnish) | 8.48e-05% | 1,179,788 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CNNM2** population constraint: LOEUF 0.312, pLI 1, missense-Z 5.0163. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hypomagnesemia, seizures, and intellectual disability 1** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 71.70, 29% of residues very-high.

**7 experimental structure(s)** (PDB): [4IY0](https://www.rcsb.org/structure/4IY0), [4IY2](https://www.rcsb.org/structure/4IY2), [4IY4](https://www.rcsb.org/structure/4IY4), [4IYS](https://www.rcsb.org/structure/4IYS), [6DJ3](https://www.rcsb.org/structure/6DJ3), [6N7E](https://www.rcsb.org/structure/6N7E).

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-08.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-08 |

## Associated conditions {#conditions}

[hypomagnesemia, seizures, and intellectual disability 1](https://sugi.bio/atlas/disease/hypomagnesemia-seizures-and-intellectual-disability-1/), [renal hypomagnesemia 6](https://sugi.bio/atlas/disease/renal-hypomagnesemia-6/).

**Reported phenotype names (ClinVar):** Hypomagnesemia, seizures, and intellectual disability 1, Renal hypomagnesemia 6, HYPOMAGNESEMIA, SEIZURES, AND IMPAIRED INTELLECTUAL DEVELOPMENT 1.

## Similar variants {#similar}

Related CNNM2 variant pages (same residue, condition, or type): [CNNM2 p.Arg602Ter](/variant/cnnm2-p-arg602ter), [CNNM2 p.Glu122Lys](/variant/cnnm2-p-glu122lys), [CNNM2 p.Glu357Lys](/variant/cnnm2-p-glu357lys), [CNNM2 p.Ser269Trp](/variant/cnnm2-p-ser269trp), [CNNM2 c.1904-6C>G](/variant/cnnm2-c-1904-minus-6c-g), [CNNM2 p.Ala45Glu](/variant/cnnm2-p-ala45glu), [CNNM2 p.Ala671Val](/variant/cnnm2-p-ala671val), [CNNM2 p.Ala874Thr](/variant/cnnm2-p-ala874thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3590489). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*