# NM_017512.7(ENOSF1):c.283C>G (p.Leu95Val)

https://sugi.bio/variant/enosf1-p-leu95val

## Summary

**ENOSF1 p.Leu95Val (c.283C>G)** is classified **Uncertain significance** in ENOSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: likely benign (0.1454); Ultra-rare (popmax 0.0111%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0111%, eas)

## For patients & families {#patients}

This is a change in the ENOSF1 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 | [ENOSF1](https://sugi.bio/atlas/gene/ENOSF1/) |
| Protein change (HGVS p.) | p.Leu95Val |
| Coding change (HGVS c.) | c.283C>G |
| MANE Select transcript | [NM_017512](https://www.ncbi.nlm.nih.gov/nuccore/NM_017512) |
| Variant type | single nucleotide variant |
| Location | chr18:697266-697266 (GRCh38) |
| ClinVar | [VCV4018078](https://www.ncbi.nlm.nih.gov/clinvar/variation/4018078/) |

**All HGVS expressions:** `NC_000018.10:g.697266G>C`, `NC_000018.9:g.697266G>C`, `NM_001318760.2:c.-263C>G`, `NM_001354065.2:c.64-2932C>G`, `NM_001354066.2:c.283C>G`, `NM_001354067.2:c.427C>G`, `NM_001354068.2:c.338-2932C>G`, `NM_017512.7:c.283C>G`, `NM_202758.5:c.427C>G`, `NR_148707.2:n.326C>G`, `NR_148709.2:n.326C>G`, `NR_148710.2:n.326C>G`, `NR_148712.2:n.470C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1454)
- REVEL 0.14 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.956 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.459, GERP 1.61, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.8**. 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 1.06** across the covering region of the MANE Select transcript (674,308–712,587), spanning 38,279 bp. Chi-square p 0.14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.25**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.25**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.21** (loss), gain 0.01 / loss 0.21. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0111%** (eas) · FAF95 0.00435% · FAF99 0.00276% · 5/44,878 in the highest group · 5/1,461,666 alleles overall — ultra-rare (popmax 0.0111%, eas).

*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}

**ENOSF1** population constraint: LOEUF 1.236, pLI 2.5469e-22, missense-Z -0.12381. *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 **95** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 97.47, 98% of residues very-high.

**1 experimental structure(s)** (PDB): [4A35](https://www.rcsb.org/structure/4A35).

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

*Describes the biological roles of ENOSF1 (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:** ENOSF1's established molecular role includes magnesium ion binding.


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

**Molecular function:** magnesium ion binding, L-fuconate dehydratase activity.

**Biological process:** carbohydrate catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-25.

**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 | 2025-04-25 |

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

## Similar variants {#similar}

Related ENOSF1 variant pages (same residue, condition, or type): [ENOSF1 c.*1219T>C](/variant/enosf1-c-star-1219t-c), [TYMS c.556+1G>A](/variant/tyms-c-556-plus-1g-a), [TYMS p.Arg271Ter](/variant/tyms-p-arg271ter), [ENOSF1 c.84+108G>C](/variant/enosf1-c-84-plus-108g-c), [ENOSF1 c.84+112A>C](/variant/enosf1-c-84-plus-112a-c), [ENOSF1 c.84+114C>G](/variant/enosf1-c-84-plus-114c-g), [ENOSF1 c.84+125T>C](/variant/enosf1-c-84-plus-125t-c), [ENOSF1 c.84+130A>C](/variant/enosf1-c-84-plus-130a-c).

### 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 4018078). 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.*