# NM_000256.3(MYBPC3):c.917G>A (p.Arg306Gln)

https://sugi.bio/variant/mybpc3-p-arg306gln

## Summary

**MYBPC3 p.Arg306Gln (c.917G>A)** is classified **Conflicting classifications of pathogenicity** in MYBPC3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-06). AlphaMissense: likely benign (0.1468); Ultra-rare (popmax 0.0173%, mid); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs373204728 · 6 submitters · 3 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0173%, mid)

## For patients & families {#patients}

This is a change in the MYBPC3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to Cardiovascular phenotype.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MYBPC3](https://sugi.bio/atlas/gene/MYBPC3/) |
| Protein change (HGVS p.) | p.Arg306Gln |
| Coding change (HGVS c.) | c.917G>A |
| MANE Select transcript | [NM_000256](https://www.ncbi.nlm.nih.gov/nuccore/NM_000256) |
| dbSNP | [rs373204728](https://www.ncbi.nlm.nih.gov/snp/rs373204728/) |
| Variant type | single nucleotide variant |
| Location | chr11:47346636-47346636 (GRCh38) |
| ClinVar | [VCV42802](https://www.ncbi.nlm.nih.gov/clinvar/variation/42802/) |

**All HGVS expressions:** `LRG_386:g.11067G>A`, `LRG_386t1:c.917G>A`, `NC_000011.10:g.47346636C>T`, `NC_000011.9:g.47368187C>T`, `NG_007667.1:g.11067G>A`, `NM_000256.3:c.917G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1468)
- REVEL 0.15 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP 7.082, GERP 2.08, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** withheld — SaProt scored this protein on a different isoform than AlphaMissense numbered the variant on, and the two diverge from residue 302, so a score under this position number would describe a different residue.
- CADD: **PHRED 23.4**. 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 0.93** across the covering region of the MANE Select transcript (47,331,874–47,352,647), spanning 20,773 bp. Chi-square p 0.0018. 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 **0.0173%** (mid) · FAF95 0.00114% · FAF99 0.000824% · 1/5,786 in the highest group · 26/1,534,606 alleles overall — ultra-rare (popmax 0.0173%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0173% | 5,786 |
| African / African-American | 0.00429% | 23,284 |
| East Asian | 0.00231% | 43,246 |
| Admixed American | 0.00187% | 53,542 |
| Finnish (not grpmax-eligible) | 0.00162% | 61,662 |
| European (non-Finnish) | 0.0016% | 62,574 |
| South Asian | 0.00115% | 86,598 |

*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}

**MYBPC3** population constraint: LOEUF 0.915, pLI 5.3289e-28, missense-Z 0.10236; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **arrhythmogenic right ventricular cardiomyopathy** — Limited (AD)
- **congenital heart disease** — Limited (AD)
- **dilated cardiomyopathy** — Limited (AD)
- **hypertrophic cardiomyopathy** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.43, 37% of residues very-high.

**17 experimental structure(s)** (PDB): [1GXE](https://www.rcsb.org/structure/1GXE), [1PD6](https://www.rcsb.org/structure/1PD6), [2AVG](https://www.rcsb.org/structure/2AVG), [2K1M](https://www.rcsb.org/structure/2K1M), [2MQ0](https://www.rcsb.org/structure/2MQ0), [2MQ3](https://www.rcsb.org/structure/2MQ3).

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

*Describes the biological roles of MYBPC3 (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:** MYBPC3's established molecular role includes structural constituent of muscle.


### Pathways affected {#pathways}

MYBPC3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | curated |

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

**Molecular function:** structural constituent of muscle, myosin binding, myosin heavy chain binding, identical protein binding.

**Biological process:** heart morphogenesis, ventricular cardiac muscle tissue morphogenesis.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-06.

**Submitter consensus:** conflicting (4 Uncertain significance, 2 Likely benign).

**Submission history:** 6 submissions (2014–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-15 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2014-02-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-04 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-06 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-23 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [cardiomyopathy](https://sugi.bio/atlas/disease/cardiomyopathy/), [hypertrophic cardiomyopathy](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not specified, not provided, Hypertrophic cardiomyopathy, Cardiomyopathy, AllHighlyPenetrant, none provided, Cardiomyopathies, HYPERTROPHIC MYOCARDIOPATHY.

## Similar variants {#similar}

Related MYBPC3 variant pages (same residue, condition, or type): [MYBPC3 p.Arg306Trp](/variant/mybpc3-p-arg306trp), [MYBPC3 p.Arg495Gln](/variant/mybpc3-p-arg495gln), [MYBPC3 p.Arg495Gly](/variant/mybpc3-p-arg495gly), [MYBPC3 p.Arg495Trp](/variant/mybpc3-p-arg495trp), [MYBPC3 p.Arg502Gln](/variant/mybpc3-p-arg502gln), [MYBPC3 c.26-2A>G](/variant/mybpc3-c-26-minus-2a-g), [MYBPC3 p.Arg1271Ter](/variant/mybpc3-p-arg1271ter), [MYBPC3 p.Lys135=](/variant/mybpc3-p-lys135).

### 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 42802). 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.*