# NM_001394062.1(MACF1):c.21300G>A (p.Val7100=)

https://sugi.bio/variant/macf1-p-val7100

## Summary

**MACF1 p.Val7100= (c.21300G>A)** is classified **Uncertain significance** in MACF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). Very rare (popmax 0.00667%, amr).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs749859918 · 2 submitters · very rare (popmax 0.00667%, amr)

## For patients & families {#patients}

This is a change in the MACF1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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.Val7100= |
| Coding change (HGVS c.) | c.21300G>A |
| MANE Select transcript | [NM_001394062](https://www.ncbi.nlm.nih.gov/nuccore/NM_001394062) |
| dbSNP | [rs749859918](https://www.ncbi.nlm.nih.gov/snp/rs749859918/) |
| Variant type | single nucleotide variant |
| Location | chr1:39459189-39459189 (GRCh38) |
| ClinVar | [VCV2723446](https://www.ncbi.nlm.nih.gov/clinvar/variation/2723446/) |

**All HGVS expressions:** `NC_000001.10:g.39924861G>A`, `NC_000001.11:g.39459189G>A`, `NG_050926.1:g.382773G>A`, `NM_001394062.1:c.21300G>A`, `NM_001397473.1:c.9378G>A`, `NM_012090.5:c.15123G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.564, GERP -3.71, phastCons 0.995 — weakly conserved position
- CADD: **PHRED 11.34**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.24**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.24**.
- Pangolin: Δ**0.22** (gain), gain 0.22 / loss 0.00. 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 **0.00667%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/59,996 in the highest group · 8/1,614,060 alleles overall — very rare (popmax 0.00667%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00667% | 14,999 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |
| African / African-American | 0.00133% | 74,930 |
| European (non-Finnish) | 0.000169% | 590,012 |

*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}

Residue **7100** lies in an α-helix; the ef-hand 2 domain.

**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. p.Val7100= falls in the ef-hand 2 domain.


### 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-12.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-25 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-12 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related MACF1 variant pages (same residue, condition, or type): [MACF1 p.Arg7251Pro](/variant/macf1-p-arg7251pro), [MACF1 p.Ala5598Ser](/variant/macf1-p-ala5598ser), [MACF1 p.Ala601Pro](/variant/macf1-p-ala601pro), [MACF1 p.Arg1196Gln](/variant/macf1-p-arg1196gln), [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).

### 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 2723446). 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.*