# NM_015047.3(EMC1):c.8C>T (p.Ala3Val)

https://sugi.bio/variant/emc1-p-ala3val

## Summary

**EMC1 p.Ala3Val (c.8C>T)** is classified **Conflicting classifications of pathogenicity** in EMC1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.1985); Ultra-rare (popmax 0.0735%, eas); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs552276163 · 3 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0735%, eas)

## For patients & families {#patients}

This is a change in the EMC1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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 | [EMC1](https://sugi.bio/atlas/gene/EMC1/) |
| Protein change (HGVS p.) | p.Ala3Val |
| Coding change (HGVS c.) | c.8C>T |
| MANE Select transcript | [NM_015047](https://www.ncbi.nlm.nih.gov/nuccore/NM_015047) |
| dbSNP | [rs552276163](https://www.ncbi.nlm.nih.gov/snp/rs552276163/) |
| Variant type | single nucleotide variant |
| Location | chr1:19251502-19251502 (GRCh38) |
| ClinVar | [VCV837771](https://www.ncbi.nlm.nih.gov/clinvar/variation/837771/) |

**All HGVS expressions:** `NC_000001.10:g.19577996G>A`, `NC_000001.11:g.19251502G>A`, `NG_032948.1:g.5058C>T`, `NM_001271427.2:c.8C>T`, `NM_001271428.2:c.8C>T`, `NM_001271429.2:c.8C>T`, `NM_001375820.1:c.8C>T`, `NM_001375821.1:c.8C>T`, `NM_015047.1:c.8C>T`, `NM_015047.3:c.8C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1985)
- REVEL 0.047 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.922 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.713, GERP 1.67, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.3**. 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.*
- Regional missense constraint: **o/e 0.95** across the covering region of the MANE Select transcript (19,235,169–19,251,509), spanning 16,340 bp. Chi-square p 0.24. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.67 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0735%** (eas) · FAF95 0.0538% · FAF99 0.047% · 33/44,886 in the highest group · 35/1,614,106 alleles overall — ultra-rare (popmax 0.0735%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0735% | 1,360 |
| European (non-Finnish) | 0.000169% | 590,012 |

*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}


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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-10.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Benign).

**Submission history:** 3 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-10 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-27 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2021-11-16 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related EMC1 variant pages (same residue, condition, or type): [EMC1 p.Thr82Met](/variant/emc1-p-thr82met), [EMC1 c.1782+3G>A](/variant/emc1-c-1782-plus-3g-a), [EMC1 c.509+6G>A](/variant/emc1-c-509-plus-6g-a), [EMC1 p.Ala152Val](/variant/emc1-p-ala152val), [EMC1 p.Ala21Thr](/variant/emc1-p-ala21thr), [EMC1 p.Ala43Val](/variant/emc1-p-ala43val), [EMC1 p.Ala509Val](/variant/emc1-p-ala509val), [EMC1 p.Ala637Thr](/variant/emc1-p-ala637thr).

### 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 837771). 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.*