# NM_020154.3(EMC7):c.229T>G (p.Phe77Val)

https://sugi.bio/variant/emc7-p-phe77val

## Summary

**EMC7 p.Phe77Val (c.229T>G)** is classified **Uncertain significance** in EMC7 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-19). AlphaMissense: likely pathogenic (0.9384); Low-frequency (popmax 2.81%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1901174527 · 1 submitter · AlphaMissense likely pathogenic · low-frequency (popmax 2.81%, nfe)

## For patients & families {#patients}

This is a change in the EMC7 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [EMC7](https://sugi.bio/atlas/gene/EMC7/) |
| Protein change (HGVS p.) | p.Phe77Val |
| Coding change (HGVS c.) | c.229T>G |
| MANE Select transcript | [NM_020154](https://www.ncbi.nlm.nih.gov/nuccore/NM_020154) |
| dbSNP | [rs1901174527](https://www.ncbi.nlm.nih.gov/snp/rs1901174527/) |
| Variant type | single nucleotide variant |
| Location | chr15:34101611-34101611 (GRCh38) |
| ClinVar | [VCV2278388](https://www.ncbi.nlm.nih.gov/clinvar/variation/2278388/) |

**All HGVS expressions:** `NC_000015.10:g.34101611A>C`, `NC_000015.9:g.34393812A>C`, `NG_130700.1:g.706A>C`, `NM_020154.3:c.229T>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9384)
- REVEL 0.804 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -10.277 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.224, GERP 1.79, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 31.0**. 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.*
- Regional missense constraint: **o/e 0.88** across the covering region of the MANE Select transcript (34,090,385–34,101,839), spanning 11,454 bp. Chi-square p 0.11. 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 (A>T, Δ0.71 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 **2.81%** (nfe) · FAF95 2.79% · FAF99 2.78% · 32,550/1,156,558 in the highest group · 37,939/1,586,290 alleles overall — low-frequency (popmax 2.81%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 2.81% | 36 |
| Remaining individuals (not grpmax-eligible) | 2.42% | 41 |
| East Asian | 2.03% | 49 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.57% | 64 |
| Middle Eastern | 1.34% | 75 |
| Finnish (not grpmax-eligible) | 1.19% | 84 |
| African / African-American | 1.05% | 95 |
| South Asian | 0.735% | 136 |
| Admixed American | 0.437% | 229 |

*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}

**EMC7** population constraint: LOEUF 0.375, pLI 0.99861, missense-Z 1.8558. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **77** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 74.54, 41% of residues very-high.

**14 experimental structure(s)** (PDB): [1B0G](https://www.rcsb.org/structure/1B0G), [1LP9](https://www.rcsb.org/structure/1LP9), [2J8U](https://www.rcsb.org/structure/2J8U), [2JCC](https://www.rcsb.org/structure/2JCC), [2UWE](https://www.rcsb.org/structure/2UWE), [6WW7](https://www.rcsb.org/structure/6WW7) — incl. mutant structure 2JCC.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-03-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-03-19 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related EMC7 variant pages (same residue, condition, or type): [EMC7 p.Gly38=](/variant/emc7-p-gly38), [EMC7 p.Ala238Pro](/variant/emc7-p-ala238pro), [EMC7 p.Ala30Val](/variant/emc7-p-ala30val), [EMC7 p.Ala31Thr](/variant/emc7-p-ala31thr), [EMC7 p.Ala4Val](/variant/emc7-p-ala4val), [EMC7 p.Arg44His](/variant/emc7-p-arg44his), [EMC7 p.Asp43Asn](/variant/emc7-p-asp43asn), [EMC7 p.Asp43His](/variant/emc7-p-asp43his).

### 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 2278388). 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.*