# NM_018100.4(EFHC1):c.1314del (p.Phe438fs)

https://sugi.bio/variant/efhc1-p-phe438fs

## Summary

**EFHC1 p.Phe438fs (c.1314del)** is classified **Pathogenic** in EFHC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2015-03-03). Very rare (popmax 0.0011%, sas).

**At a glance:** Pathogenic · review: Single submitter · rsID rs796052421 · 1 submitter · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the EFHC1 gene that is reported as disease-causing, but on limited review, 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 | [EFHC1](https://sugi.bio/atlas/gene/EFHC1/) |
| Protein change (HGVS p.) | p.Phe438fs |
| Coding change (HGVS c.) | c.1314del |
| MANE Select transcript | [NM_018100](https://www.ncbi.nlm.nih.gov/nuccore/NM_018100) |
| dbSNP | [rs796052421](https://www.ncbi.nlm.nih.gov/snp/rs796052421/) |
| Variant type | Deletion |
| Location | chr6:52479070-52479070 (GRCh38) |
| ClinVar | [VCV205420](https://www.ncbi.nlm.nih.gov/clinvar/variation/205420/) |

**All HGVS expressions:** `NC_000006.11:g.52343870del`, `NC_000006.12:g.52479072del`, `NG_016760.1:g.63877del`, `NM_001172420.2:c.1257del`, `NM_018100.3:c.1312del`, `NM_018100.3:c.1312delT`, `NM_018100.4:c.1314del`, `NR_033327.2:n.2640del`

## 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 -0.491, GERP -3.55 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.906, pLI 2.4306e-13. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 11**, so the transcript is predicted to undergo NMD.
- 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 **0.0011%** (sas) · 1/91,076 in the highest group · 1/1,461,752 alleles overall — very rare (popmax 0.0011%, sas).

*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}

**EFHC1** population constraint: LOEUF 0.906, pLI 2.4306e-13, missense-Z 1.3019. *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):

- **epilepsy** — Refuted (AD)

## Protein context {#protein}

Residue **438** lies in the dm10 3 domain.

AlphaFold model confidence (whole protein): pLDDT 84.31, 44% of residues very-high.

**2 experimental structure(s)** (PDB): [7UNG](https://www.rcsb.org/structure/7UNG), [8J07](https://www.rcsb.org/structure/8J07).

## What this gene does {#gene-function}

*Describes the biological roles of EFHC1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** EFHC1's established molecular role includes alpha-tubulin binding. p.Phe438fs falls in the dm10 3 domain.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** alpha-tubulin binding.

**Biological process:** mitotic cytokinesis, mitotic spindle organization, cerebral cortex cell migration, regulation of cell division.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2015-03-03.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2015-03-03 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related EFHC1 variant pages (same residue, condition, or type): [EFHC1 p.Asp228fs](/variant/efhc1-p-asp228fs), [EFHC1 p.Gln395fs](/variant/efhc1-p-gln395fs), [EFHC1 p.Ile367fs](/variant/efhc1-p-ile367fs), [EFHC1 p.Asp167fs](/variant/efhc1-p-asp167fs), [EFHC1 p.Asp363fs](/variant/efhc1-p-asp363fs), [EFHC1 p.Glu391fs](/variant/efhc1-p-glu391fs), [EFHC1 p.Ile122_Tyr123del](/variant/efhc1-p-ile122-tyr123del), [EFHC1 c.1138-293del](/variant/efhc1-c-1138-minus-293del).

### 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 205420). 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.*