# NM_022336.4(EDAR):c.723G>A (p.Glu241=)

https://sugi.bio/variant/edar-p-glu241

## Summary

**EDAR p.Glu241= (c.723G>A)** is classified **Benign/Likely benign** in EDAR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-15). Low-frequency (popmax 3.04%, eas); Associated with hypohidrotic ectodermal dysplasia.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs3749108 · 5 submitters · 4 linked conditions · low-frequency (popmax 3.04%, eas)

## For patients & families {#patients}

This is a change in the EDAR gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to hypohidrotic ectodermal dysplasia.

*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, X-linked recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | EDAR is a diagnostic-grade gene on 4 Genomics England panels |

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

- Abnormality of the dentition — Very frequent (99-80%)
- Hypoplasia of the maxilla — Very frequent (99-80%)
- Dry skin — Very frequent (99-80%)
- Thin skin — Very frequent (99-80%)
- Keratoconjunctivitis sicca — Very frequent (99-80%)
- Abnormal facial shape — Very frequent (99-80%)
- Abnormal dental morphology — Very frequent (99-80%)
- Irregular hyperpigmentation — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000076/index) · [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.Glu241= |
| Coding change (HGVS c.) | c.723G>A |
| MANE Select transcript | [NM_022336](https://www.ncbi.nlm.nih.gov/nuccore/NM_022336) |
| dbSNP | [rs3749108](https://www.ncbi.nlm.nih.gov/snp/rs3749108/) |
| Variant type | single nucleotide variant |
| Location | chr2:108910783-108910783 (GRCh38) |
| ClinVar | [VCV463881](https://www.ncbi.nlm.nih.gov/clinvar/variation/463881/) |

**All HGVS expressions:** `NC_000002.11:g.109527239C>T`, `NC_000002.12:g.108910783C>T`, `NG_008257.1:g.83590G>A`, `NM_022336.4:c.723G>A`

## 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 0.933, GERP -1.95, phastCons 0.509 — weakly conserved position
- CADD: **PHRED 6.96**. 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 **3.04%** (eas) · FAF95 2.9% · FAF99 2.85% · 1,361/44,830 in the highest group · 10,992/1,613,166 alleles overall — low-frequency (popmax 3.04%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 3.04% | 33 |
| South Asian | 1.95% | 51 |
| Remaining individuals (not grpmax-eligible) | 0.639% | 156 |
| European (non-Finnish) | 0.592% | 169 |
| Middle Eastern | 0.494% | 202 |
| Admixed American | 0.473% | 211 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.152% | 658 |
| African / African-American | 0.107% | 937 |
| Finnish (not grpmax-eligible) | 0.0641% | 1,559 |

*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 **241** lies in the 'disordered' region.

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.Glu241= falls in the disordered region.


### 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-15.

**Submitter consensus:** conflicting (4 Benign, 1 Likely benign).

**Submission history:** 5 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-11 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-15 |

## Associated conditions {#conditions}

[hypohidrotic ectodermal dysplasia](https://sugi.bio/atlas/disease/hypohidrotic-ectodermal-dysplasia/), [ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant](https://sugi.bio/atlas/disease/ectodermal-dysplasia-10a-hypohidrotic-hair-nail-type-autosomal-dominant/), [ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive](https://sugi.bio/atlas/disease/ectodermal-dysplasia-10b-hypohidrotic-hair-tooth-type-autosomal-recessive/), [autosomal recessive hypohidrotic ectodermal dysplasia](https://sugi.bio/atlas/disease/autosomal-recessive-hypohidrotic-ectodermal-dysplasia/).

**Reported phenotype names (ClinVar):** Hypohidrotic ectodermal dysplasia, Autosomal recessive hypohidrotic ectodermal dysplasia syndrome, Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant, not provided, Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive, HAIR MORPHOLOGY 1, none provided, Autosomal recessive hypohidrotic ectodermal dysplasia, Ectodermal Dysplasia 3, Anhidrotic, HAIR THICKNESS, VARIATION IN.

## Similar variants {#similar}

Related EDAR variant pages (same residue, condition, or type): [EDAR p.Glu241Ala](/variant/edar-p-glu241ala), [EDAR c.730+1G>T](/variant/edar-c-730-plus-1g-t), [EDAR p.Ala26Val](/variant/edar-p-ala26val), [EDAR p.Arg25Ter](/variant/edar-p-arg25ter), [EDAR p.Arg358Ter](/variant/edar-p-arg358ter), [EDAR p.Arg420Gln](/variant/edar-p-arg420gln), [EDAR p.Arg89His](/variant/edar-p-arg89his), [EDAR p.Arg98Trp](/variant/edar-p-arg98trp).

### 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 463881). 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.*