# NM_053025.4(MYLK):c.5477C>T (p.Ala1826Val)

https://sugi.bio/variant/mylk-p-ala1826val

## Summary

**MYLK p.Ala1826Val (c.5477C>T)** is classified **Conflicting classifications of pathogenicity** in MYLK (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-02-02). AlphaMissense: ambiguous (0.3611); Ultra-rare (popmax 0.0987%, mid); Associated with familial thoracic aortic aneurysm and aortic dissection.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs147187907 · 15 submitters · 2 linked conditions · AlphaMissense ambiguous · ultra-rare (popmax 0.0987%, mid)

## For patients & families {#patients}

This is a change in the MYLK gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 15 submitters, and is linked to familial thoracic aortic aneurysm and aortic dissection.

*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 dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MYLK is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Familial thoracic aortic aneurysm and aortic dissection** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Cutis marmorata — Very frequent (99-80%)
- Abnormality of connective tissue — Very frequent (99-80%)
- Cystic medial necrosis of the aorta — Very frequent (99-80%)
- Abnormality iris morphology — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Cardiomegaly — Frequent (79-30%)
- Aortic regurgitation — Frequent (79-30%)
- Coronaryartery atherosclerosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002249/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MYLK](https://sugi.bio/atlas/gene/MYLK/) |
| Protein change (HGVS p.) | p.Ala1826Val |
| Coding change (HGVS c.) | c.5477C>T |
| MANE Select transcript | [NM_053025](https://www.ncbi.nlm.nih.gov/nuccore/NM_053025) |
| dbSNP | [rs147187907](https://www.ncbi.nlm.nih.gov/snp/rs147187907/) |
| Variant type | single nucleotide variant |
| Location | chr3:123618662-123618662 (GRCh38) |
| ClinVar | [VCV252775](https://www.ncbi.nlm.nih.gov/clinvar/variation/252775/) |

**All HGVS expressions:** `NC_000003.11:g.123337509G>A`, `NC_000003.12:g.123618662G>A`, `NG_029111.1:g.270641C>T`, `NM_001321309.2:c.4949C>T`, `NM_053025.4:c.5477C>T`, `NM_053026.4:c.5270C>T`, `NM_053027.4:c.5324C>T`, `NM_053028.4:c.5117C>T`, `NM_053031.4:c.194C>T`, `NM_053032.4:c.197C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3611) — no call either way
- REVEL 0.342 (indeterminate)
- SaProt LLR -7.613 (tolerated)
- Conservation: phyloP 11.861, GERP 2.08, phastCons 1 — highly conserved
- CADD: **PHRED 29.3**. 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 0.67** across the covering region of the MANE Select transcript (123,614,108–123,664,178), spanning 50,070 bp. Chi-square p 2.5e-20. 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 **0.0987%** (mid) · FAF95 0.0701% · FAF99 0.0684% · 6/6,080 in the highest group · 953/1,613,984 alleles overall — ultra-rare (popmax 0.0987%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0987% | 1,013 |
| European (non-Finnish) | 0.0742% | 1,349 |
| Remaining individuals (not grpmax-eligible) | 0.0432% | 2,314 |
| South Asian | 0.0351% | 2,846 |
| African / African-American | 0.00934% | 10,702 |
| Admixed American | 0.005% | 20,002 |
| Finnish (not grpmax-eligible) | 0.00469% | 21,337 |

*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}

**MYLK** population constraint: LOEUF 0.604, pLI 1.1732e-12, missense-Z 3.1672; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **familial thoracic aortic aneurysm and aortic dissection** — Strong (AD)

## Protein context {#protein}

Residue **1826** lies in a UniProt-annotated variant site (in aat7; uncertain significance); the ig-like c2-type 9 domain.

AlphaFold model confidence (whole protein): pLDDT 66.54, 19% of residues very-high.

**8 experimental structure(s)** (PDB): [2CQV](https://www.rcsb.org/structure/2CQV), [2YR3](https://www.rcsb.org/structure/2YR3), [5JQA](https://www.rcsb.org/structure/5JQA), [5JTH](https://www.rcsb.org/structure/5JTH), [6C6M](https://www.rcsb.org/structure/6C6M), [9MVW](https://www.rcsb.org/structure/9MVW).

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

*Describes the biological roles of MYLK (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:** MYLK's established molecular role includes myosin light chain kinase activity. p.Ala1826Val falls in the ig-like c2-type 9 domain.


### Pathways affected {#pathways}

MYLK participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | curated |
| [RHO GTPases activate PAKs](https://reactome.org/content/detail/R-HSA-5627123) | electronic |

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

**Molecular function:** myosin light chain kinase activity, scaffold protein binding.

**Biological process:** positive regulation of cell migration, bleb assembly, positive regulation of calcium ion transport, aorta smooth muscle tissue morphogenesis, cellular hypotonic response, positive regulation of wound healing.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (12 Uncertain significance, 2 Likely benign, 1 Uncertain Significance).

**Submission history:** 15 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-12-17 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-27 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-03-07 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-09 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Uncertain significance | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-03-09 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-02 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain Significance | criteria provided, single submitter | clinical testing | 2025-07-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-04 |

## Associated conditions {#conditions}

[familial thoracic aortic aneurysm and aortic dissection](https://sugi.bio/atlas/disease/familial-thoracic-aortic-aneurysm-and-aortic-dissection/), [aortic aneurysm, familial thoracic 7](https://sugi.bio/atlas/disease/aortic-aneurysm-familial-thoracic-7/).

**Reported phenotype names (ClinVar):** Familial thoracic aortic aneurysm and aortic dissection, Aortic aneurysm, familial thoracic 7, not provided, not specified, MYLK-related disorder, MYLK-related condition, AllHighlyPenetrant, none provided, Thoracic aortic aneurysms and dissections, AORTIC DISSECTION, FAMILIAL, WITH OR WITHOUT AORTIC ANEURYSM.

## Similar variants {#similar}

Related MYLK variant pages (same residue, condition, or type): [MYLK c.2390+1G>A](/variant/mylk-c-2390-plus-1g-a), [MYLK p.Arg1275Ter](/variant/mylk-p-arg1275ter), [MYLK p.Arg1480Ter](/variant/mylk-p-arg1480ter), [MYLK c.1310-1G>A](/variant/mylk-c-1310-minus-1g-a), [MYLK c.1652-2A>C](/variant/mylk-c-1652-minus-2a-c), [MYLK c.1804+5G>T](/variant/mylk-c-1804-plus-5g-t), [MYLK c.2140+5G>C](/variant/mylk-c-2140-plus-5g-c), [MYLK c.2462+3G>A](/variant/mylk-c-2462-plus-3g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 252775). 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.*