# NM_007074.4(CORO1A):c.909C>T (p.Phe303=)

https://sugi.bio/variant/coro1a-p-phe303

## Summary

**CORO1A p.Phe303= (c.909C>T)** is classified **Likely benign** in CORO1A (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-02). Very rare (popmax 8.47e-05%, nfe); Associated with severe combined immunodeficiency due to CORO1A deficiency.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CORO1A gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to severe combined immunodeficiency due to CORO1A deficiency.

*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) | Childhood, Infancy, Neonatal |
| Diagnostic panels | CORO1A is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017144/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CORO1A](https://sugi.bio/atlas/gene/CORO1A/) |
| Protein change (HGVS p.) | p.Phe303= |
| Coding change (HGVS c.) | c.909C>T |
| MANE Select transcript | [NM_007074](https://www.ncbi.nlm.nih.gov/nuccore/NM_007074) |
| Variant type | single nucleotide variant |
| Location | chr16:30187989-30187989 (GRCh38) |
| ClinVar | [VCV4740070](https://www.ncbi.nlm.nih.gov/clinvar/variation/4740070/) |

**All HGVS expressions:** `LRG_195:g.9385C>T`, `LRG_195t1:c.909C>T`, `NC_000016.10:g.30187989C>T`, `NC_000016.9:g.30199310C>T`, `NG_023415.1:g.9385C>T`, `NM_001193333.3:c.909C>T`, `NM_007074.4:c.909C>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 4.074, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.62**. 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, Δ0.36 acceptor 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 **8.47e-05%** (nfe) · 1/1,180,018 in the highest group · 1/1,461,828 alleles overall — very rare (popmax 8.47e-05%, 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}

**CORO1A** population constraint: LOEUF 0.572, pLI 0.70891, missense-Z 3.0728; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **severe combined immunodeficiency due to CORO1A deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.25, 87% of residues very-high.

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

*Describes the biological roles of CORO1A (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:** CORO1A's established molecular role includes RNA binding. In Reactome, CORO1A is annotated in disease pathway(s) including **Prevention of phagosomal-lysosomal fusion**.

**Disease mechanism (Reactome):** CORO1A loss or alteration is curated in [Prevention of phagosomal-lysosomal fusion](https://reactome.org/content/detail/R-HSA-9636383).

### Pathways affected {#pathways}

CORO1A participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Prevention of phagosomal-lysosomal fusion](https://reactome.org/content/detail/R-HSA-9636383) | other |

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

**Molecular function:** RNA binding, actin binding, actin monomer binding, myosin heavy chain binding, protein homodimerization activity, phosphatidylinositol 3-kinase binding.

**Biological process:** phagolysosome assembly, phagocytosis, actin cytoskeleton organization, cell-substrate adhesion, regulation of actin cytoskeleton organization, natural killer cell degranulation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-02.

**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 | 2026-01-02 |

## Associated conditions {#conditions}

[severe combined immunodeficiency due to CORO1A deficiency](https://sugi.bio/atlas/disease/severe-combined-immunodeficiency-due-to-coro1a-deficiency/).

**Reported phenotype names (ClinVar):** Severe combined immunodeficiency due to CORO1A deficiency, Immunodeficiency 8, IMMUNODEFICIENCY 8 WITH LYMPHOPROLIFERATION.

## Similar variants {#similar}

Related CORO1A variant pages (same residue, condition, or type): [CORO1A p.Ala385Val](/variant/coro1a-p-ala385val), [CORO1A p.Arg186Gln](/variant/coro1a-p-arg186gln), [CORO1A p.Arg293Gln](/variant/coro1a-p-arg293gln), [CORO1A p.Arg293Trp](/variant/coro1a-p-arg293trp), [CORO1A p.Gly413Arg](/variant/coro1a-p-gly413arg), [CORO1A p.His92Gln](/variant/coro1a-p-his92gln), [CORO1A p.Leu116Pro](/variant/coro1a-p-leu116pro), [CORO1A p.Met167Thr](/variant/coro1a-p-met167thr).

### 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 4740070). 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.*