# NM_012431.3(SEMA3E):c.1731T>C (p.Phe577=)

https://sugi.bio/variant/sema3e-p-phe577

## Summary

**SEMA3E p.Phe577= (c.1731T>C)** is classified **Likely benign** in SEMA3E (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-17). Very rare (popmax 0.000424%, nfe); Associated with CHARGE syndrome.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the SEMA3E gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to CHARGE 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.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000029/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SEMA3E](https://sugi.bio/atlas/gene/SEMA3E/) |
| Protein change (HGVS p.) | p.Phe577= |
| Coding change (HGVS c.) | c.1731T>C |
| MANE Select transcript | [NM_012431](https://www.ncbi.nlm.nih.gov/nuccore/NM_012431) |
| Variant type | single nucleotide variant |
| Location | chr7:83386987-83386987 (GRCh38) |
| ClinVar | [VCV4780339](https://www.ncbi.nlm.nih.gov/clinvar/variation/4780339/) |

**All HGVS expressions:** `LRG_1287:g.267177T>C`, `LRG_1287t1:c.1731T>C`, `NC_000007.13:g.83016303A>G`, `NC_000007.14:g.83386987A>G`, `NG_021242.2:g.267177T>C`, `NM_001178129.2:c.1551T>C`, `NM_012431.3:c.1731T>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 1.839, GERP -0.259, phastCons 0.994 — weakly conserved position
- CADD: **PHRED 9.44**. 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 (A>C, Δ0.82 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 **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,179,510 in the highest group · 5/1,613,198 alleles overall — very rare (popmax 0.000424%, nfe).

*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}

**SEMA3E** population constraint: LOEUF 0.668, pLI 2.7748e-06, missense-Z 1.1196. *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):

- **CHARGE syndrome** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.62, 67% of residues very-high.

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

*Describes the biological roles of SEMA3E (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:** SEMA3E's established molecular role includes semaphorin receptor binding.


### Pathways affected {#pathways}

SEMA3E participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Other semaphorin interactions](https://reactome.org/content/detail/R-HSA-416700) | curated |

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

**Molecular function:** semaphorin receptor binding, receptor ligand activity.

**Biological process:** gonadotrophin-releasing hormone neuronal migration to the hypothalamus, negative regulation of neuron apoptotic process, positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction, semaphorin-plexin signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-17.

**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 | 2025-09-17 |

## Associated conditions {#conditions}

[CHARGE syndrome](https://sugi.bio/atlas/disease/charge-syndrome/).

**Reported phenotype names (ClinVar):** CHARGE syndrome, Hittner Hirsch Kreh syndrome, Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies, CHARGE association, Hall-Hittner syndrome, CHARGE ASSOCIATION--COLOBOMA, HEART ANOMALY, CHOANAL ATRESIA, RETARDATION, GENITAL AND EAR ANOMALIES.

## Similar variants {#similar}

Related SEMA3E variant pages (same residue, condition, or type): [SEMA3E c.1500+5G>A](/variant/sema3e-c-1500-plus-5g-a), [SEMA3E p.Ala112Val](/variant/sema3e-p-ala112val), [SEMA3E p.Ala290Val](/variant/sema3e-p-ala290val), [SEMA3E p.Ala383Ser](/variant/sema3e-p-ala383ser), [SEMA3E p.Ala414Thr](/variant/sema3e-p-ala414thr), [SEMA3E p.Ala437Thr](/variant/sema3e-p-ala437thr), [SEMA3E p.Ala508Thr](/variant/sema3e-p-ala508thr), [SEMA3E p.Ala609Val](/variant/sema3e-p-ala609val).

### 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 4780339). 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.*