# NM_153717.3(EVC):c.2805G>A (p.Arg935=)

https://sugi.bio/variant/evc-p-arg935

## Summary

**EVC p.Arg935= (c.2805G>A)** is classified **Conflicting classifications of pathogenicity** in EVC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-13). Rare (popmax 0.115%, afr); Associated with acrofacial dysostosis, Weyers type.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs143631233 · 5 submitters · 2 linked conditions · rare (popmax 0.115%, afr)

## 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 5 submitters, and is linked to acrofacial dysostosis, Weyers type.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000497/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.Arg935= |
| Coding change (HGVS c.) | c.2805G>A |
| MANE Select transcript | [NM_153717](https://www.ncbi.nlm.nih.gov/nuccore/NM_153717) |
| dbSNP | [rs143631233](https://www.ncbi.nlm.nih.gov/snp/rs143631233/) |
| Variant type | single nucleotide variant |
| Location | chr4:5810361-5810361 (GRCh38) |
| ClinVar | [VCV733306](https://www.ncbi.nlm.nih.gov/clinvar/variation/733306/) |

**All HGVS expressions:** `NC_000004.11:g.5812088G>A`, `NC_000004.12:g.5810361G>A`, `NG_008843.1:g.104165G>A`, `NM_001306090.2:c.2805G>A`, `NM_153717.3:c.2805G>A`

## 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 0.924, GERP -0.497, phastCons 1 — weakly conserved position
- CADD: **PHRED 3.742**. 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 (G>T, Δ0.31 acceptor loss), 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 **0.115%** (afr) · FAF95 0.095% · FAF99 0.0878% · 86/75,052 in the highest group · 103/1,613,806 alleles overall — rare (popmax 0.115%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.115% | 873 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,813 |
| Admixed American | 0.00334% | 29,984 |
| European (non-Finnish) | 0.000593% | 168,561 |

*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}

Residue **935** lies in the 'disordered' region.

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 2026-01-13.

**Submitter consensus:** conflicting (3 Likely benign, 2 Uncertain significance).

**Submission history:** 5 submissions (2018–2026); 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 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2019-11-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-03 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-13 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-01-11 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Curry-Hall syndrome, Ellis-van Creveld syndrome, not specified, WEYERS ACRODENTAL DYSOSTOSIS, Chondroectodermal dysplasia, MESOECTODERMAL DYSPLASIA, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **935** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [EVC p.Arg935fs](/variant/evc-p-arg935fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related EVC variant pages (same residue, condition, or type): [EVC p.Arg935fs](/variant/evc-p-arg935fs), [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).

### 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 733306). 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.*