# NM_001256545.2(MEGF10):c.2477C>T (p.Ala826Val)

https://sugi.bio/variant/megf10-p-ala826val

## Summary

**MEGF10 p.Ala826Val (c.2477C>T)** is classified **Uncertain significance** in MEGF10 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: likely benign (0.0909); Ultra-rare (popmax 0.0165%, mid); Associated with MEGF10-related myopathy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs150095036 · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the MEGF10 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Ala826Val |
| Coding change (HGVS c.) | c.2477C>T |
| MANE Select transcript | [NM_001256545](https://www.ncbi.nlm.nih.gov/nuccore/NM_001256545) |
| dbSNP | [rs150095036](https://www.ncbi.nlm.nih.gov/snp/rs150095036/) |
| Variant type | single nucleotide variant |
| Location | chr5:127443112-127443112 (GRCh38) |
| ClinVar | [VCV539960](https://www.ncbi.nlm.nih.gov/clinvar/variation/539960/) |

**All HGVS expressions:** `NC_000005.10:g.127443112C>T`, `NC_000005.9:g.126778804C>T`, `NG_032072.2:g.157349C>T`, `NM_001256545.2:c.2477C>T`, `NM_032446.3:c.2477C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0909)
- REVEL 0.341 (indeterminate)
- SaProt LLR -7.177 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 7.656, GERP 1.87, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.2**. 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 0.26** across the covering region of the MANE Select transcript (127,443,082–127,445,463), spanning 2,381 bp — the region is depleted of missense variation. Chi-square p 0.00031. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.00893% · FAF99 0.00837% · 1/6,068 in the highest group · 134/1,612,786 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,068 |
| European (non-Finnish) | 0.0104% | 9,588 |
| East Asian | 0.00669% | 14,957 |
| Admixed American | 0.005% | 19,984 |
| South Asian | 0.0022% | 45,439 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,420 |
| African / African-American | 0.00134% | 74,840 |

*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 **826** lies in the egf-like 15 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.Ala826Val falls in the egf-like 15 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** MEGF10-related myopathy, Congenital myopathy 10A, severe variant.

## Similar variants {#similar}

Related MEGF10 variant pages (same residue, condition, or type): [MEGF10 p.Ala826Thr](/variant/megf10-p-ala826thr), [MEGF10 p.Ala826=](/variant/megf10-p-ala826), [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), [MEGF10 p.Ala171Thr](/variant/megf10-p-ala171thr).

### 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 539960). 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.*