# NM_001256545.2(MEGF10):c.917G>A (p.Arg306Gln)

https://sugi.bio/variant/megf10-p-arg306gln

## Summary

**MEGF10 p.Arg306Gln (c.917G>A)** is classified **Conflicting classifications of pathogenicity** in MEGF10 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-03). AlphaMissense: likely benign (0.2127); Ultra-rare (popmax 0.012%, afr); Associated with MEGF10-related myopathy.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs986353158 · 2 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.012%, afr)

## For patients & families {#patients}

This is a change in the MEGF10 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to MEGF10-related myopathy.

*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) | Infancy, Neonatal |
| Diagnostic panels | MEGF10 is a diagnostic-grade gene on 6 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012199/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MEGF10](https://sugi.bio/atlas/gene/MEGF10/) |
| Protein change (HGVS p.) | p.Arg306Gln |
| Coding change (HGVS c.) | c.917G>A |
| MANE Select transcript | [NM_001256545](https://www.ncbi.nlm.nih.gov/nuccore/NM_001256545) |
| dbSNP | [rs986353158](https://www.ncbi.nlm.nih.gov/snp/rs986353158/) |
| Variant type | single nucleotide variant |
| Location | chr5:127402682-127402682 (GRCh38) |
| ClinVar | [VCV1314583](https://www.ncbi.nlm.nih.gov/clinvar/variation/1314583/) |

**All HGVS expressions:** `NC_000005.10:g.127402682G>A`, `NC_000005.9:g.126738374G>A`, `NG_032072.2:g.116919G>A`, `NM_001256545.2:c.917G>A`, `NM_001308119.2:c.917G>A`, `NM_001308121.2:c.917G>A`, `NM_032446.3:c.917G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2127)
- REVEL 0.277 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.552 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.72) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 11.898, GERP 0.93, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 35.0**. 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 0.90** across the covering region of the MANE Select transcript (127,331,309–127,443,081), spanning 111,772 bp. Chi-square p 0.0013. 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 **0.72**, acceptor gain **0.00**, donor gain **0.02**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.72**, acceptor gain **0.00**, donor gain **0.02**.
- Pangolin: Δ**0.63** (loss), gain 0.01 / loss 0.63. 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 **0.012%** (afr) · FAF95 0.00624% · FAF99 0.00468% · 9/74,892 in the highest group · 17/1,613,690 alleles overall — ultra-rare (popmax 0.012%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.012% | 8,321 |
| Admixed American | 0.00334% | 29,978 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,474 |
| South Asian | 0.0011% | 91,004 |
| European (non-Finnish) | 0.000339% | 294,969 |

*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}

**MEGF10** population constraint: LOEUF 0.707, pLI 1e-12, missense-Z 2.0865. *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):

- **MEGF10-related myopathy** — Definitive (AR)

## Protein context {#protein}

Residue **306** lies in the egf-like 5 domain; the 'necessary for interaction with ap2m1, self-assembly and formation of the irregular, mosaic-like adhesion pattern' region.

AlphaFold model confidence (whole protein): pLDDT 70.73, 1% of residues very-high.

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

*Describes the biological roles of MEGF10 (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:** MEGF10's established molecular role includes complement component C1q complex binding. p.Arg306Gln falls in the egf-like 5 domain.


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

**Molecular function:** complement component C1q complex binding, scavenger receptor activity, Notch binding.

**Biological process:** skeletal muscle satellite cell differentiation, positive regulation of cell-cell adhesion, muscle cell proliferation, homotypic cell-cell adhesion, regulation of skeletal muscle tissue development, regulation of muscle cell differentiation.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-02-03.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-02-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-05 |

## Associated conditions {#conditions}

[MEGF10-related myopathy](https://sugi.bio/atlas/disease/megf10-related-myopathy/).

**Reported phenotype names (ClinVar):** MEGF10-related myopathy, not provided, none provided, Congenital myopathy 10A, severe variant.

## Similar variants {#similar}

Related MEGF10 variant pages (same residue, condition, or type): [MEGF10 p.Arg306Trp](/variant/megf10-p-arg306trp), [MEGF10 p.Arg306=](/variant/megf10-p-arg306), [MEGF10 p.Arg306Pro](/variant/megf10-p-arg306pro), [MEGF10 c.2104+1G>T](/variant/megf10-c-2104-plus-1g-t), [MEGF10 p.Cys774Arg](/variant/megf10-p-cys774arg), [MEGF10 p.Glu398Ter](/variant/megf10-p-glu398ter), [MEGF10 c.1426+5G>T](/variant/megf10-c-1426-plus-5g-t), [MEGF10 c.*1170G>A](/variant/megf10-c-star-1170g-a).

### 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 1314583). 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.*