# NM_177986.5(DSG4):c.21A>G (p.Arg7=)

https://sugi.bio/variant/dsg4-p-arg7

## Summary

**DSG4 p.Arg7= (c.21A>G)** is classified **Benign/Likely benign** in DSG4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-10). Low-frequency (popmax 3.58%, afr); Associated with hypotrichosis 6.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs75549650 · 3 submitters · 1 linked condition · low-frequency (popmax 3.58%, afr)

## For patients & families {#patients}

This is a change in the DSG4 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to hypotrichosis 6.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Childhood |

**Commonly reported features of Hypotrichosis simplex** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sparse eyelashes — Very frequent (99-80%)
- Alopecia — Very frequent (99-80%)
- Sparse scalp hair — Very frequent (99-80%)
- Sparse body hair — Very frequent (99-80%)
- Sparse eyebrow — Very frequent (99-80%)
- Sparse hair — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015423/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DSG4](https://sugi.bio/atlas/gene/DSG4/) |
| Protein change (HGVS p.) | p.Arg7= |
| Coding change (HGVS c.) | c.21A>G |
| dbSNP | [rs75549650](https://www.ncbi.nlm.nih.gov/snp/rs75549650/) |
| Variant type | single nucleotide variant |
| Location | chr18:31376932-31376932 (GRCh38) |
| ClinVar | [VCV326415](https://www.ncbi.nlm.nih.gov/clinvar/variation/326415/) |

**All HGVS expressions:** `NC_000018.10:g.31376932A>G`, `NC_000018.9:g.28956895A>G`, `NG_013040.1:g.5156A>G`, `NM_001134453.3:c.21A>G`, `NM_177986.5:c.21A>G`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.956, GERP -3.97, phastCons 0.996 — weakly conserved position
- CADD: **PHRED 4.702**. 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.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **3.58%** (afr) · FAF95 3.47% · FAF99 3.42% · 2,684/75,014 in the highest group · 2,896/1,613,664 alleles overall — low-frequency (popmax 3.58%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 3.58% | 28 |
| Remaining individuals (not grpmax-eligible) | 0.182% | 548 |
| Middle Eastern | 0.132% | 758 |
| Admixed American | 0.112% | 895 |
| European (non-Finnish) | 0.00186% | 53,624 |
| South Asian | 0.0011% | 91,070 |

*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.*

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-10.

**Submitter consensus:** conflicting (2 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-02-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-10-10 |

## Associated conditions {#conditions}

[hypotrichosis 6](https://sugi.bio/atlas/disease/hypotrichosis-6/).

**Reported phenotype names (ClinVar):** Hypotrichosis 6, not provided, DSG4-related disorder, DSG4-related condition, none provided, HYPOTRICHOSIS, LOCALIZED, AUTOSOMAL RECESSIVE 1, MONILETHRIX-LIKE HYPOTRICHOSIS.

### 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 326415). 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.*