# NM_018341.3(ERMARD):c.846C>T (p.Phe282=)

https://sugi.bio/variant/ermard-p-phe282

## Summary

**ERMARD p.Phe282= (c.846C>T)** is classified **Benign** in ERMARD (ClinVar, Single submitter, 2 submitters; last evaluated 2024-08-28). Rare (popmax 0.327%, afr).

**At a glance:** Benign · review: Single submitter · rsID rs138733309 · 2 submitters · rare (popmax 0.327%, afr)

## For patients & families {#patients}

This is a change in the ERMARD gene that is classified as benign — not considered disease-causing, submitted by 2 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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ERMARD](https://sugi.bio/atlas/gene/ERMARD/) |
| Protein change (HGVS p.) | p.Phe282= |
| Coding change (HGVS c.) | c.846C>T |
| MANE Select transcript | [NM_018341](https://www.ncbi.nlm.nih.gov/nuccore/NM_018341) |
| dbSNP | [rs138733309](https://www.ncbi.nlm.nih.gov/snp/rs138733309/) |
| Variant type | single nucleotide variant |
| Location | chr6:169760745-169760745 (GRCh38) |
| ClinVar | [VCV787844](https://www.ncbi.nlm.nih.gov/clinvar/variation/787844/) |

**All HGVS expressions:** `NC_000006.11:g.170160841C>T`, `NC_000006.12:g.169760745C>T`, `NG_033842.1:g.14124C>T`, `NM_001278531.2:c.846C>T`, `NM_001278532.2:c.468C>T`, `NM_001278533.2:c.846C>T`, `NM_018341.3:c.846C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.50) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.266, GERP 4.28, phastCons 0.011 — weakly conserved position
- CADD: **PHRED 1.268**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.50**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.50**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.34** (loss), gain 0.00 / loss 0.34. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.327%** (afr) · FAF95 0.293% · FAF99 0.28% · 245/74,970 in the highest group · 265/1,611,898 alleles overall — rare (popmax 0.327%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.327% | 306 |
| Middle Eastern | 0.033% | 3,029 |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,244 |
| Admixed American | 0.00834% | 11,997 |
| European (non-Finnish) | 0.000255% | 392,699 |

*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}

**ERMARD** population constraint: LOEUF 0.996, pLI 1.5088e-16, missense-Z 0.047435. *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):

- **periventricular nodular heterotopia** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.79, 77% of residues very-high.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-28.

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

**Submission history:** 2 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-09-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2024-08-28 |

**Reported phenotype names (ClinVar):** not provided, ERMARD-related disorder, ERMARD-related condition, none provided.

## Similar variants {#similar}

Related ERMARD variant pages (same residue, condition, or type): [ERMARD p.Ala474Val](/variant/ermard-p-ala474val), [ERMARD p.Arg367His](/variant/ermard-p-arg367his), [ERMARD p.Arg400Ser](/variant/ermard-p-arg400ser), [ERMARD p.Arg537Gln](/variant/ermard-p-arg537gln), [ERMARD p.Arg544Cys](/variant/ermard-p-arg544cys), [ERMARD p.Arg569Cys](/variant/ermard-p-arg569cys), [ERMARD p.Arg571Gln](/variant/ermard-p-arg571gln), [ERMARD p.Arg571Trp](/variant/ermard-p-arg571trp).

### 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 787844). 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.*