# NM_017828.5(COMMD4):c.226C>G (p.Leu76Val)

https://sugi.bio/variant/commd4-p-leu76val

## Summary

**COMMD4 p.Leu76Val (c.226C>G)** is classified **Uncertain significance** in COMMD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). AlphaMissense: likely benign (0.1592); Very rare (popmax 0.00333%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the COMMD4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COMMD4](https://sugi.bio/atlas/gene/COMMD4/) |
| Protein change (HGVS p.) | p.Leu76Val |
| Coding change (HGVS c.) | c.226C>G |
| MANE Select transcript | [NM_017828](https://www.ncbi.nlm.nih.gov/nuccore/NM_017828) |
| Variant type | single nucleotide variant |
| Location | chr15:75339029-75339029 (GRCh38) |
| ClinVar | [VCV3268924](https://www.ncbi.nlm.nih.gov/clinvar/variation/3268924/) |

**All HGVS expressions:** `NC_000015.10:g.75339029C>G`, `NC_000015.9:g.75631370C>G`, `NM_001284377.2:c.226C>G`, `NM_001284378.2:c.226C>G`, `NM_001284379.2:c.244C>G`, `NM_001321844.2:c.154C>G`, `NM_001321845.2:c.88C>G`, `NM_001321846.2:c.160C>G`, `NM_001321847.2:c.160C>G`, `NM_001321848.2:c.244C>G`, `NM_017828.5:c.226C>G`, `NR_104312.2:n.253C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1592)
- REVEL 0.124 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -10.044 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- SpliceAI predicts **acceptor loss** (Δ 0.36) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.825, GERP 1.36, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.6**. 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 0.97** across the covering region of the MANE Select transcript (75,336,090–75,340,002), spanning 3,912 bp. Chi-square p 0.66. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.36**, donor loss **0.00**, acceptor gain **0.09**, donor gain **0.00**. Largest is acceptor loss, 8 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.09**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/59,996 in the highest group · 3/1,613,776 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 29,998 |
| East Asian | 0.00223% | 44,896 |

*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}

**COMMD4** population constraint: LOEUF 0.982, pLI 9.6051e-05, missense-Z 0.11956. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **76** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 80.85, 8% of residues very-high.

**4 experimental structure(s)** (PDB): [8F2R](https://www.rcsb.org/structure/8F2R), [8F2U](https://www.rcsb.org/structure/8F2U), [8P0W](https://www.rcsb.org/structure/8P0W), [9ZMZ](https://www.rcsb.org/structure/9ZMZ).

## What this gene does {#gene-function}

*Describes the biological roles of COMMD4 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

COMMD4 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-20 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related COMMD4 variant pages (same residue, condition, or type): [COMMD4 p.Ala103Thr](/variant/commd4-p-ala103thr), [COMMD4 p.Ala103Val](/variant/commd4-p-ala103val), [COMMD4 p.Ala132Thr](/variant/commd4-p-ala132thr), [COMMD4 p.Ala163Thr](/variant/commd4-p-ala163thr), [COMMD4 p.Ala191Thr](/variant/commd4-p-ala191thr), [COMMD4 p.Arg108His](/variant/commd4-p-arg108his), [COMMD4 p.Arg122Trp](/variant/commd4-p-arg122trp), [COMMD4 p.Arg127Gly](/variant/commd4-p-arg127gly).

### 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 3268924). 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.*