# NM_147127.5(EVC2):c.1261_1262insTATACACATCTGTGATC (p.Ser421fs)

https://sugi.bio/variant/evc2-p-ser421fs

## Summary

**EVC2 p.Ser421fs (c.1261_1262insTATACACATCTGTGATC)** is classified **Likely pathogenic** in EVC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-03). No gnomAD frequency available for this variant; Associated with Ellis-van Creveld syndrome.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2475438548 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the EVC2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Ellis-van Creveld syndrome.

*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/0001301/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EVC2](https://sugi.bio/atlas/gene/EVC2/) |
| Protein change (HGVS p.) | p.Ser421fs |
| Coding change (HGVS c.) | c.1261_1262insTATACACATCTGTGATC |
| MANE Select transcript | [NM_147127](https://www.ncbi.nlm.nih.gov/nuccore/NM_147127) |
| dbSNP | [rs2475438548](https://www.ncbi.nlm.nih.gov/snp/rs2475438548/) |
| Variant type | Insertion |
| Location | chr4:5640722-5640723 (GRCh38) |
| ClinVar | [VCV1724940](https://www.ncbi.nlm.nih.gov/clinvar/variation/1724940/) |

**All HGVS expressions:** `NC_000004.11:g.5642449_5642450insGATCACAGATGTGTATA`, `NC_000004.12:g.5640722_5640723insGATCACAGATGTGTATA`, `NG_015821.2:g.73825_73826insTATACACATCTGTGATC`, `NG_083282.1:g.1107_1108insGATCACAGATGTGTATA`, `NM_001166136.2:c.1021_1022insTATACACATCTGTGATC`, `NM_147127.5:c.1261_1262insTATACACATCTGTGATC`

## 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 6.041, GERP 0.307, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.092, pLI 1.7773e-47. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 22**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**EVC2** population constraint: LOEUF 1.092, pLI 1.7773e-47, missense-Z -1.7856; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **acrofacial dysostosis, Weyers type** — Definitive (AD)
- **Ellis-van Creveld syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.33, 35% of residues very-high.

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

*Describes the biological roles of EVC2 (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.*


### Pathways affected {#pathways}

EVC2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of SMO](https://reactome.org/content/detail/R-HSA-5635838) | other |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | other |

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-03.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-03 |

## Associated conditions {#conditions}

[Ellis-van Creveld syndrome](https://sugi.bio/atlas/disease/ellis-van-creveld-syndrome/).

**Reported phenotype names (ClinVar):** Ellis-van Creveld syndrome, EVC-Related Ellis-van Creveld Syndrome, EVC2-Related Ellis-van Creveld Syndrome, MESOECTODERMAL DYSPLASIA, Chondroectodermal dysplasia.

## Similar variants {#similar}

Related EVC2 variant pages (same residue, condition, or type): [EVC2 p.Ser421=](/variant/evc2-p-ser421), [EVC2 p.Arg676fs](/variant/evc2-p-arg676fs), [EVC2 p.Asp1181fs](/variant/evc2-p-asp1181fs), [EVC2 p.Asp448Ter](/variant/evc2-p-asp448ter), [EVC2 p.Gln518fs](/variant/evc2-p-gln518fs), [EVC2 p.Trp1213fs](/variant/evc2-p-trp1213fs), [EVC2 c.2707-7_2707-6insA](/variant/evc2-c-2707-minus-7-2707-minus-6insa), [EVC2 c.3659+17_3659+18insGGGGA](/variant/evc2-c-3659-plus-17-3659-plus-18insgggga).

### 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 1724940). 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.*