# NM_177986.5(DSG4):c.574T>C (p.Ser192Pro)

https://sugi.bio/variant/dsg4-p-ser192pro

## Summary

**DSG4 p.Ser192Pro (c.574T>C)** is classified **Pathogenic** in DSG4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2006-06-01). AlphaMissense: likely pathogenic (0.9968); Ultra-rare (popmax 0.0134%, eas); Associated with hypotrichosis 6.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs267606775 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0134%, eas)

## For patients & families {#patients}

This is a change in the DSG4 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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 |
| Diagnostic panels | DSG4 is a diagnostic-grade gene on 3 Genomics England panels |

**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.Ser192Pro |
| Coding change (HGVS c.) | c.574T>C |
| MANE Select transcript | [NM_177986](https://www.ncbi.nlm.nih.gov/nuccore/NM_177986) |
| dbSNP | [rs267606775](https://www.ncbi.nlm.nih.gov/snp/rs267606775/) |
| Variant type | single nucleotide variant |
| Location | chr18:31390712-31390712 (GRCh38) |
| ClinVar | [VCV2721](https://www.ncbi.nlm.nih.gov/clinvar/variation/2721/) |

**All HGVS expressions:** `NC_000018.10:g.31390712T>C`, `NC_000018.9:g.28970675T>C`, `NG_013040.1:g.18936T>C`, `NM_001134453.3:c.574T>C`, `NM_177986.5:c.574T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9968) — concordant with the pathogenic call
- REVEL 0.567 (indeterminate)
- SaProt LLR -13.543 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.919, GERP 1.99, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in DSG4 (of 6,125 modeled).
- CADD: **PHRED 26.4**. 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 1.07** across the covering region of the MANE Select transcript (31,376,912–31,413,592), spanning 36,680 bp. Chi-square p 0.015. 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 **0.0134%** (eas) · FAF95 0.00579% · FAF99 0.00394% · 6/44,860 in the highest group · 6/1,613,632 alleles overall — ultra-rare (popmax 0.0134%, eas).

*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}

**DSG4** population constraint: LOEUF 1.061, pLI 6.2985e-24, missense-Z -0.23289; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 **192** lies in a UniProt-annotated variant site (in hypt6); the cadherin 2 domain.

AlphaFold model confidence (whole protein): pLDDT 65.63, 33% of residues very-high.

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

*Describes the biological roles of DSG4 (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}

DSG4 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of the cornified envelope](https://reactome.org/content/detail/R-HSA-6809371) | curated |
| [Keratinization](https://reactome.org/content/detail/R-HSA-6805567) | curated |

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2006-06-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2006-06-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hypotrichosis 6, HYPOTRICHOSIS, LOCALIZED, AUTOSOMAL RECESSIVE 1, MONILETHRIX-LIKE HYPOTRICHOSIS.

## Similar variants {#similar}

Related DSG4 variant pages (same residue, condition, or type): [DSG4 p.His386Gln](/variant/dsg4-p-his386gln), [DSG4 p.His902Arg](/variant/dsg4-p-his902arg), [DSG4 p.Tyr585His](/variant/dsg4-p-tyr585his), [DSG4 c.*126G>A](/variant/dsg4-c-star-126g-a), [DSG4 c.*31C>T](/variant/dsg4-c-star-31c-t), [DSG4 p.Ala154Thr](/variant/dsg4-p-ala154thr), [DSG4 p.Ile439Thr](/variant/dsg4-p-ile439thr), [DSG4 p.Met1023Ile](/variant/dsg4-p-met1023ile).

### 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 2721). 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.*