# NM_153717.3(EVC):c.1074C>T (p.Cys358=)

https://sugi.bio/variant/evc-p-cys358

## Summary

**EVC p.Cys358= (c.1074C>T)** is classified **Conflicting classifications of pathogenicity** in EVC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-24). Very rare (popmax 0.0011%, sas); Associated with Ellis-van Creveld syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs921573510 · 2 submitters · 2 linked conditions · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the EVC gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, 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 | [EVC](https://sugi.bio/atlas/gene/EVC/) |
| Protein change (HGVS p.) | p.Cys358= |
| Coding change (HGVS c.) | c.1074C>T |
| MANE Select transcript | [NM_153717](https://www.ncbi.nlm.nih.gov/nuccore/NM_153717) |
| dbSNP | [rs921573510](https://www.ncbi.nlm.nih.gov/snp/rs921573510/) |
| Variant type | single nucleotide variant |
| Location | chr4:5748282-5748282 (GRCh38) |
| ClinVar | [VCV907729](https://www.ncbi.nlm.nih.gov/clinvar/variation/907729/) |

**All HGVS expressions:** `NC_000004.11:g.5750009C>T`, `NC_000004.12:g.5748282C>T`, `NG_008843.1:g.42086C>T`, `NM_001306090.2:c.1074C>T`, `NM_001306092.2:c.1074C>T`, `NM_153717.3:c.1074C>T`

## 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 -9.043, GERP -3.94 — fast-evolving / accelerated position
- CADD: **PHRED 1.526**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.22 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 **0.0011%** (sas) · FAF95 0.000247% · FAF99 0.000159% · 1/91,070 in the highest group · 12/1,613,932 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0135% | 7,401 |
| South Asian (grpmax) | 0.0011% | 91,070 |
| European (non-Finnish) | 0.000593% | 168,571 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**EVC** population constraint: LOEUF 1.134, pLI 6.2955e-37, missense-Z -1.5572. *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):

- **Ellis-van Creveld syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.49, 41% of residues very-high.

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

*Describes the biological roles of EVC (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}

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

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

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-01-24.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-24 |

## Associated conditions {#conditions}

[Ellis-van Creveld syndrome](https://sugi.bio/atlas/disease/ellis-van-creveld-syndrome/), [acrofacial dysostosis, Weyers type](https://sugi.bio/atlas/disease/acrofacial-dysostosis-weyers-type/).

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

## Similar variants {#similar}

Related EVC variant pages (same residue, condition, or type): [EVC c.1098+1G>A](/variant/evc-c-1098-plus-1g-a), [EVC c.175-2A>G](/variant/evc-c-175-minus-2a-g), [EVC c.1777-1G>A](/variant/evc-c-1777-minus-1g-a), [EVC c.1777-2A>G](/variant/evc-c-1777-minus-2a-g), [EVC c.1886+1G>C](/variant/evc-c-1886-plus-1g-c), [EVC c.1886+5G>A](/variant/evc-c-1886-plus-5g-a), [EVC c.1886+5G>T](/variant/evc-c-1886-plus-5g-t), [EVC c.2304+2T>C](/variant/evc-c-2304-plus-2t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 907729). 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.*