# NM_015047.3(EMC1):c.2619_2622del (p.Pro874fs)

https://sugi.bio/variant/emc1-p-pro874fs

## Summary

**EMC1 p.Pro874fs (c.2619_2622del)** is classified **Pathogenic/Likely pathogenic** in EMC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-16). Very rare (popmax 0.00334%, amr); Associated with congenital anomaly of kidney and urinary tract.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs869320624 · 4 submitters · 2 linked conditions · very rare (popmax 0.00334%, amr)

## For patients & families {#patients}

This is a change in the EMC1 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to congenital anomaly of kidney and urinary tract.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019216/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EMC1](https://sugi.bio/atlas/gene/EMC1/) |
| Protein change (HGVS p.) | p.Pro874fs |
| Coding change (HGVS c.) | c.2619_2622del |
| MANE Select transcript | [NM_015047](https://www.ncbi.nlm.nih.gov/nuccore/NM_015047) |
| dbSNP | [rs869320624](https://www.ncbi.nlm.nih.gov/snp/rs869320624/) |
| Variant type | Deletion |
| Location | chr1:19220814-19220817 (GRCh38) |
| ClinVar | [VCV219099](https://www.ncbi.nlm.nih.gov/clinvar/variation/219099/) |

**All HGVS expressions:** `NC_000001.10:g.19547311_19547314del`, `NC_000001.11:g.19220817_19220820del`, `NG_032948.1:g.35743_35746del`, `NM_001271427.2:c.2616_2619del`, `NM_001271428.2:c.2616_2619del`, `NM_001271429.2:c.2553_2556del`, `NM_015047.3:c.2619_2622del`

## 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 7.928, GERP 2.06, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.913, pLI 1.0051e-25. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 21 of 23**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 36.0**. 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** — 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 **0.00334%** (amr) · FAF95 0.000554% · FAF99 0.000207% · 2/59,932 in the highest group · 2/151,596 alleles overall — very rare (popmax 0.00334%, amr).

*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}

**EMC1** population constraint: LOEUF 0.913, pLI 1.0051e-25, missense-Z 2.3619. *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):

- **complex neurodevelopmental disorder with motor features** — Moderate (AR)
- **complex neurodevelopmental disorder with motor features** — Moderate (AD)

## Protein context {#protein}

Residue **874** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 87.67, 68% of residues very-high.

**10 experimental structure(s)** (PDB): [6WW7](https://www.rcsb.org/structure/6WW7), [6Z3W](https://www.rcsb.org/structure/6Z3W), [7ADO](https://www.rcsb.org/structure/7ADO), [7ADP](https://www.rcsb.org/structure/7ADP), [8EOI](https://www.rcsb.org/structure/8EOI), [8J0N](https://www.rcsb.org/structure/8J0N).

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-02-16.

**Submitter consensus:** conflicting (3 Pathogenic, 2 Likely pathogenic).

**Submission history:** 5 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2016-03-29 |
| Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Likely pathogenic | flagged submission | research |  |
| Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Likely pathogenic | criteria provided, single submitter | research |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-12-29 |
| Laboratory of Genetics, Children's Clinical University Hospital Latvia | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-16 |

## Associated conditions {#conditions}

[congenital anomaly of kidney and urinary tract](https://sugi.bio/atlas/disease/congenital-anomaly-of-kidney-and-urinary-tract/), [cerebellar atrophy, visual impairment, and psychomotor retardation;](https://sugi.bio/atlas/disease/cerebellar-atrophy-visual-impairment-and-psychomotor-retardation/).

**Reported phenotype names (ClinVar):** Congenital anomaly of kidney and urinary tract, Cerebellar atrophy, visual impairment, and psychomotor retardation;, not provided, none provided, Cerebellar atrophy, visual impairment, and psychomotor retardation, Congenital anomalies of the kidney and urinary tract, Congenital anomalies of kidney and urinary tract.

## Similar variants {#similar}

Related EMC1 variant pages (same residue, condition, or type): [EMC1 p.Asn739fs](/variant/emc1-p-asn739fs), [EMC1 p.Pro874His](/variant/emc1-p-pro874his), [EMC1 p.Val564fs](/variant/emc1-p-val564fs), [EMC1 c.2675_2676del](/variant/emc1-c-2675-2676del), [EMC1 c.287-1G>A](/variant/emc1-c-287-minus-1g-a), [EMC1 c.787-1G>A](/variant/emc1-c-787-minus-1g-a), [EMC1 p.Arg660Ter](/variant/emc1-p-arg660ter), [EMC1 p.Arg69Ter](/variant/emc1-p-arg69ter).

### 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 219099). 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.*