# NM_022336.4(EDAR):c.1072C>T (p.Arg358Ter)

https://sugi.bio/variant/edar-p-arg358ter

## Summary

**EDAR p.Arg358Ter (c.1072C>T)** is classified **Pathogenic** in EDAR (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-05). Very rare (popmax 8.47e-05%, nfe); Associated with EDAR-related disorder.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs121908452 · 9 submitters · 3 linked conditions · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the EDAR gene that is considered disease-causing, submitted by 9 submitters, and is linked to EDAR-related disorder.

*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 | [EDAR](https://sugi.bio/atlas/gene/EDAR/) |
| Protein change (HGVS p.) | p.Arg358Ter |
| Coding change (HGVS c.) | c.1072C>T |
| MANE Select transcript | [NM_022336](https://www.ncbi.nlm.nih.gov/nuccore/NM_022336) |
| dbSNP | [rs121908452](https://www.ncbi.nlm.nih.gov/snp/rs121908452/) |
| Variant type | single nucleotide variant |
| Location | chr2:108897182-108897182 (GRCh38) |
| ClinVar | [VCV5852](https://www.ncbi.nlm.nih.gov/clinvar/variation/5852/) |

**All HGVS expressions:** `NC_000002.11:g.109513638G>A`, `NC_000002.12:g.108897182G>A`, `NG_008257.1:g.97191C>T`, `NM_022336.4:c.1072C>T`

## Computational & population evidence {#evidence}

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

- **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 4.15, GERP 1.05, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.927, pLI 1.243e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (12 of 12)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 42.0**. 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 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 **8.47e-05%** (nfe) · 1/1,180,028 in the highest group · 1/1,461,552 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**EDAR** population constraint: LOEUF 0.927, pLI 1.243e-09, missense-Z 1.2955. *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):

- **ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive** — Definitive (AR)

## Protein context {#protein}

Residue **358** lies in a UniProt-annotated variant site (in ectd10b); the death domain.

AlphaFold model confidence (whole protein): pLDDT 67.01, 14% of residues very-high.

**1 experimental structure(s)** (PDB): [7X9G](https://www.rcsb.org/structure/7X9G).

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

*Describes the biological roles of EDAR (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.*

**How this variant is thought to act:** EDAR's established molecular role includes transmembrane signaling receptor activity. p.Arg358Ter falls in the death domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [TNFs bind their physiological receptors](https://reactome.org/content/detail/R-HSA-5669034) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transmembrane signaling receptor activity.

**Biological process:** cytokine-mediated signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-05.

**Submitter consensus:** unanimous (9/9 Pathogenic).

**Submission history:** 9 submissions (1999–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1999-08-01 |
| Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Pathogenic | criteria provided, single submitter | research | 2026-06-05 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-21 |
| Department of Prosthodontics, Peking University School and Hospital of Stomatology | Pathogenic | no assertion criteria provided | clinical testing | 2020-04-27 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-09 |
| Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-08 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-02-02 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-01 |

## Associated conditions {#conditions}

[EDAR-related disorder](https://sugi.bio/atlas/disease/edar-related-disorder/), [ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant](https://sugi.bio/atlas/disease/ectodermal-dysplasia-10a-hypohidrotic-hair-nail-type-autosomal-dominant/), [autosomal recessive hypohidrotic ectodermal dysplasia](https://sugi.bio/atlas/disease/autosomal-recessive-hypohidrotic-ectodermal-dysplasia/).

**Reported phenotype names (ClinVar):** EDAR-related disorder, Ectodermal dysplasia 10a, hypohidrotic/hair/tooth type, autosomal dominant, not provided, Autosomal recessive hypohidrotic ectodermal dysplasia syndrome, Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant, Non-syndromic oligodontia, EDAR-related condition, Autosomal recessive hypohidrotic ectodermal dysplasia, Ectodermal Dysplasia 3, Anhidrotic, none provided.

## Similar variants {#similar}

Related EDAR variant pages (same residue, condition, or type): [EDAR p.Ala26Val](/variant/edar-p-ala26val), [EDAR p.Arg25Ter](/variant/edar-p-arg25ter), [EDAR p.Arg420Gln](/variant/edar-p-arg420gln), [EDAR p.Arg89His](/variant/edar-p-arg89his), [EDAR p.Arg98Trp](/variant/edar-p-arg98trp), [EDAR p.Cys301Ter](/variant/edar-p-cys301ter), [EDAR p.Cys428Arg](/variant/edar-p-cys428arg), [EDAR p.Gly382Ser](/variant/edar-p-gly382ser).

### 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 5852). 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.*