# NM_005215.4(DCC):c.2000G>A (p.Arg667His)

https://sugi.bio/variant/dcc-p-arg667his

## Summary

**DCC p.Arg667His (c.2000G>A)** is classified **Benign/Likely benign** in DCC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-10-01). AlphaMissense: likely benign (0.1751); Low-frequency (popmax 1.06%, mid).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs200099519 · 4 submitters · 1 linked condition · AlphaMissense likely benign · low-frequency (popmax 1.06%, mid)

## For patients & families {#patients}

This is a change in the DCC gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters.

*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/0015086/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DCC](https://sugi.bio/atlas/gene/DCC/) |
| Protein change (HGVS p.) | p.Arg667His |
| Coding change (HGVS c.) | c.2000G>A |
| MANE Select transcript | [NM_005215](https://www.ncbi.nlm.nih.gov/nuccore/NM_005215) |
| dbSNP | [rs200099519](https://www.ncbi.nlm.nih.gov/snp/rs200099519/) |
| Variant type | single nucleotide variant |
| Location | chr18:53305666-53305666 (GRCh38) |
| ClinVar | [VCV187791](https://www.ncbi.nlm.nih.gov/clinvar/variation/187791/) |

**All HGVS expressions:** `LRG_1107:g.970495G>A`, `LRG_1107t1:c.2000G>A`, `NC_000018.10:g.53305666G>A`, `NC_000018.9:g.50832036G>A`, `NG_013341.2:g.970495G>A`, `NM_005215.4:c.2000G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1751)
- REVEL 0.421 (indeterminate)
- Conservation: phyloP 9.926, GERP 2.84, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** withheld — SaProt scored this protein on a different isoform than AlphaMissense numbered the variant on, and the two diverge from residue 178, so a score under this position number would describe a different residue.
- CADD: **PHRED 28.1**. 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 0.98** across the covering region of the MANE Select transcript (52,340,788–53,530,591), spanning 1,189,803 bp. Chi-square p 0.4. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **1.06%** (mid) · FAF95 0.849% · FAF99 0.773% · 64/6,060 in the highest group · 1,284/1,613,934 alleles overall — low-frequency (popmax 1.06%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 1.06% | 95 |
| South Asian | 0.842% | 119 |
| Remaining individuals (not grpmax-eligible) | 0.122% | 822 |
| Admixed American | 0.0383% | 2,609 |
| European (non-Finnish) | 0.0287% | 3,480 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0236% | 4,229 |
| African / African-American | 0.008% | 12,506 |
| East Asian | 0.00223% | 44,874 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,020 |

*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}

**DCC** population constraint: LOEUF 0.414, pLI 1, missense-Z 0.97556. *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):

- **mirror movements 1 and/or agenesis of the corpus callosum** — Definitive (AD)

## Protein context {#protein}

Residue **667** lies in the fibronectin type-iii 3 domain; a UniProt-annotated variant site (in mrmv1; likely pathogenic); a β-strand.

AlphaFold model confidence (whole protein): pLDDT 68.60, 26% of residues very-high.

**9 experimental structure(s)** (PDB): [2ED7](https://www.rcsb.org/structure/2ED7), [2ED8](https://www.rcsb.org/structure/2ED8), [2ED9](https://www.rcsb.org/structure/2ED9), [2EDB](https://www.rcsb.org/structure/2EDB), [2EDD](https://www.rcsb.org/structure/2EDD), [2EDE](https://www.rcsb.org/structure/2EDE).

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

*Describes the biological roles of DCC (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}

DCC participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Caspase activation via Dependence Receptors in the absence of ligand](https://reactome.org/content/detail/R-HSA-418889) | curated |
| [DCC mediated attractive signaling](https://reactome.org/content/detail/R-HSA-418885) | electronic |
| [DSCAM interactions](https://reactome.org/content/detail/R-HSA-376172) | electronic |
| [Netrin mediated repulsion signals](https://reactome.org/content/detail/R-HSA-418886) | electronic |
| [Netrin-1 signaling](https://reactome.org/content/detail/R-HSA-373752) | electronic |
| [Regulation of commissural axon pathfinding by SLIT and ROBO](https://reactome.org/content/detail/R-HSA-428542) | electronic |
| [Role of second messengers in netrin-1 signaling](https://reactome.org/content/detail/R-HSA-418890) | electronic |

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-10-01.

**Submitter consensus:** conflicting (2 Benign, 1 Likely benign, 1 not provided).

**Submission history:** 4 submissions (2019–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| GeneReviews | not provided | no classification provided | literature only |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

MONDO:0008002.

**Reported phenotype names (ClinVar):** Mirror movements 1, not provided, none provided.

## Similar variants {#similar}

Related DCC variant pages (same residue, condition, or type): [DCC p.Arg1025Ter](/variant/dcc-p-arg1025ter), [DCC p.Arg275Ter](/variant/dcc-p-arg275ter), [DCC p.Arg879Ter](/variant/dcc-p-arg879ter), [DCC p.Gly803Arg](/variant/dcc-p-gly803arg), [DCC c.2053+13A>G](/variant/dcc-c-2053-plus-13a-g), [DCC c.2053+9T>C](/variant/dcc-c-2053-plus-9t-c), [DCC c.3130+10A>G](/variant/dcc-c-3130-plus-10a-g), [DCC c.91+7G>A](/variant/dcc-c-91-plus-7g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 187791). 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.*