# NM_001003787.4(STRADA):c.118A>C (p.Arg40=)

https://sugi.bio/variant/strada-p-arg40

## Summary

**STRADA p.Arg40= (c.118A>C)** is classified **Likely benign** in STRADA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). Absent from gnomAD v4.1; Associated with polyhydramnios, megalencephaly, and symptomatic epilepsy.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the STRADA gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to polyhydramnios, megalencephaly, and symptomatic epilepsy.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Diagnostic panels | STRADA is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Polyhydramnios-megalencephaly-symptomatic epilepsy syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Macrocephaly — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Megalencephaly — Very frequent (99-80%)
- Polyhydramnios — Very frequent (99-80%)
- Abnormal facial shape — Very frequent (99-80%)
- Infantile spasms — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012913/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STRADA](https://sugi.bio/atlas/gene/STRADA/) |
| Protein change (HGVS p.) | p.Arg40= |
| Coding change (HGVS c.) | c.118A>C |
| MANE Select transcript | [NM_001003787](https://www.ncbi.nlm.nih.gov/nuccore/NM_001003787) |
| Variant type | single nucleotide variant |
| Location | chr17:63723303-63723303 (GRCh38) |
| ClinVar | [VCV3640288](https://www.ncbi.nlm.nih.gov/clinvar/variation/3640288/) |

**All HGVS expressions:** `NC_000017.10:g.61800663T>G`, `NC_000017.11:g.63723303T>G`, `NG_015817.1:g.23668A>C`, `NM_001003786.3:c.12+5055A>C`, `NM_001003787.4:c.118A>C`, `NM_001003788.3:c.-52+3335A>C`, `NM_001165969.2:c.36+5031A>C`, `NM_001165970.2:c.94+3335A>C`, `NM_001363786.1:c.94A>C`, `NM_001363787.1:c.36+5031A>C`, `NM_001363788.1:c.118A>C`, `NM_001363789.1:c.12+5055A>C`, `NM_001363790.1:c.-52+3335A>C`, `NM_001363791.1:c.-52+3335A>C`, `NM_001411083.1:c.118A>C`, `NM_001411084.1:c.36+5031A>C`, `NM_001411085.1:c.118A>C`, `NM_153335.6:c.12+5055A>C`, `NR_156741.2:n.221A>C`

## 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 7.887, GERP 2.03, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.43**. 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 (T>C, Δ0.28 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**STRADA** population constraint: LOEUF 0.649, pLI 0.0078763, missense-Z 1.9204. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.46, 64% of residues very-high.

**4 experimental structure(s)** (PDB): [1UPK](https://www.rcsb.org/structure/1UPK), [2WTK](https://www.rcsb.org/structure/2WTK), [3GNI](https://www.rcsb.org/structure/3GNI), [8VSU](https://www.rcsb.org/structure/8VSU).

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

*Describes the biological roles of STRADA (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:** STRADA's established molecular role includes kinase binding.


### Pathways affected {#pathways}

STRADA participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Energy dependent regulation of mTOR by LKB1-AMPK](https://reactome.org/content/detail/R-HSA-380972) | other |

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

**Molecular function:** kinase binding, protein kinase activator activity, protein serine/threonine kinase activator activity.

**Biological process:** protein export from nucleus, activation of protein kinase activity, G1 to G0 transition.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-12 |

## Associated conditions {#conditions}

[polyhydramnios, megalencephaly, and symptomatic epilepsy](https://sugi.bio/atlas/disease/polyhydramnios-megalencephaly-and-symptomatic-epilepsy/).

**Reported phenotype names (ClinVar):** Polyhydramnios, megalencephaly, and symptomatic epilepsy, PMSE SYNDROME.

## Similar variants {#similar}

Related STRADA variant pages (same residue, condition, or type): [STRADA p.Arg40Lys](/variant/strada-p-arg40lys), [STRADA c.36+1G>A](/variant/strada-c-36-plus-1g-a), [STRADA c.37-1G>C](/variant/strada-c-37-minus-1g-c), [STRADA p.Arg228Ter](/variant/strada-p-arg228ter), [STRADA p.Ala45Val](/variant/strada-p-ala45val), [STRADA p.Arg100Gln](/variant/strada-p-arg100gln), [STRADA p.Arg13Gln](/variant/strada-p-arg13gln), [STRADA p.Arg13Leu](/variant/strada-p-arg13leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 3640288). 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.*