# NM_001394062.1(MACF1):c.13688G>A (p.Arg4563Gln)

https://sugi.bio/variant/macf1-p-arg4563gln

## Summary

**MACF1 p.Arg4563Gln (c.13688G>A)** is classified **Likely benign** in MACF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-11). AlphaMissense: likely benign (0.1342); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Multiple submitters · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.004%, afr)

## For patients & families {#patients}

This is a change in the MACF1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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 | [MACF1](https://sugi.bio/atlas/gene/MACF1/) |
| Protein change (HGVS p.) | p.Arg4563Gln |
| Coding change (HGVS c.) | c.13688G>A |
| MANE Select transcript | [NM_001394062](https://www.ncbi.nlm.nih.gov/nuccore/NM_001394062) |
| Variant type | single nucleotide variant |
| Location | chr1:39381992-39381992 (GRCh38) |
| ClinVar | [VCV4102049](https://www.ncbi.nlm.nih.gov/clinvar/variation/4102049/) |

**All HGVS expressions:** `NC_000001.10:g.39847664G>A`, `NC_000001.11:g.39381992G>A`, `NG_050926.1:g.305576G>A`, `NM_001394062.1:c.13688G>A`, `NM_012090.5:c.7502G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1342)
- REVEL 0.566 (indeterminate)
- Conservation: phyloP 11.766, GERP 2.27, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R4568Q** vs ClinVar **R4563Q**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 24.0**. 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 0.87** across the covering region of the MANE Select transcript (39,349,483–39,442,566), spanning 93,083 bp. Chi-square p 4.8e-14. 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 **0.004%** (afr) · FAF95 0.00275% · FAF99 0.00244% · 3/74,910 in the highest group · 52/1,613,812 alleles overall — very rare (popmax 0.004%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,621 |
| African / African-American (grpmax) | 0.004% | 24,970 |
| European (non-Finnish) | 0.00364% | 27,442 |
| Finnish (not grpmax-eligible) | 0.00313% | 31,913 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**MACF1** population constraint: LOEUF 0.238, pLI 1, missense-Z 6.219. *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):

- **lissencephaly spectrum disorder with complex brainstem malformation** — Moderate (AD)

## Protein context {#protein}


**3 experimental structure(s)** (PDB): [4Z6G](https://www.rcsb.org/structure/4Z6G), [5VE9](https://www.rcsb.org/structure/5VE9), [5X57](https://www.rcsb.org/structure/5X57).

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

*Describes the biological roles of MACF1 (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:** MACF1's established molecular role includes RNA binding.


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

**Molecular function:** RNA binding, actin binding, cadherin binding, microtubule minus-end binding, actin filament binding.

**Biological process:** regulation of cell migration, regulation of microtubule-based process, Golgi to plasma membrane protein transport, positive regulation of axon extension, regulation of focal adhesion assembly.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-11.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-11 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-03-29 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related MACF1 variant pages (same residue, condition, or type): [MACF1 p.Ala5598Ser](/variant/macf1-p-ala5598ser), [MACF1 p.Ala601Pro](/variant/macf1-p-ala601pro), [MACF1 p.Arg30Gln](/variant/macf1-p-arg30gln), [MACF1 p.Arg3713Cys](/variant/macf1-p-arg3713cys), [MACF1 p.Arg4674Cys](/variant/macf1-p-arg4674cys), [MACF1 p.Arg5490Gln](/variant/macf1-p-arg5490gln), [MACF1 p.Arg5875Cys](/variant/macf1-p-arg5875cys), [MACF1 p.Arg6864Gln](/variant/macf1-p-arg6864gln).

### 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 4102049). 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.*