# NM_018341.3(ERMARD):c.1483_1485del (p.Cys495del)

https://sugi.bio/variant/ermard-p-cys495del

## Summary

**ERMARD p.Cys495del (c.1483_1485del)** is classified **Uncertain significance** in ERMARD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-02). Very rare (popmax 0.00223%, eas); Associated with periventricular nodular heterotopia 6.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the ERMARD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to periventricular nodular heterotopia 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015983/index) · [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.Cys495del |
| Coding change (HGVS c.) | c.1483_1485del |
| MANE Select transcript | [NM_018341](https://www.ncbi.nlm.nih.gov/nuccore/NM_018341) |
| Variant type | Deletion |
| Location | chr6:169776026-169776028 (GRCh38) |
| ClinVar | [VCV3891398](https://www.ncbi.nlm.nih.gov/clinvar/variation/3891398/) |

**All HGVS expressions:** `NC_000006.11:g.170176124_170176126del`, `NC_000006.12:g.169776028_169776030del`, `NG_033842.1:g.29407_29409del`, `NM_001278531.2:c.1483_1485del`, `NM_001278532.2:c.1105_1107del`, `NM_001278533.2:c.1483_1485del`, `NM_001410957.1:c.1075_1077del`, `NM_018341.3:c.1483_1485del`

## 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 0.154, GERP -3.65 — weakly conserved position
- Molecular consequence: **in-frame indel**.
- CADD: **PHRED 0.035**. 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** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000124% · FAF99 9e-05% · 1/44,904 in the highest group · 7/1,614,056 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,904 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |
| European (non-Finnish) | 0.000424% | 236,008 |

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-02.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | research | 2022-11-02 |

## Associated conditions {#conditions}

[periventricular nodular heterotopia 6](https://sugi.bio/atlas/disease/periventricular-nodular-heterotopia-6/).

**Reported phenotype names (ClinVar):** Periventricular nodular heterotopia 6.

## Similar variants {#similar}

Related ERMARD variant pages (same residue, condition, or type): [ERMARD c.1521-82del](/variant/ermard-c-1521-minus-82del), [ERMARD p.Arg544fs](/variant/ermard-p-arg544fs), [ERMARD p.Asp358fs](/variant/ermard-p-asp358fs), [ERMARD p.His476fs](/variant/ermard-p-his476fs), [ERMARD p.Pro504fs](/variant/ermard-p-pro504fs), [ERMARD p.Tyr636fs](/variant/ermard-p-tyr636fs), [ERMARD p.Glu105Gly](/variant/ermard-p-glu105gly), [ERMARD p.Thr211Met](/variant/ermard-p-thr211met).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3891398). 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.*