Is MYLK p.Ala1826Val (c.5477C>T) pathogenic?

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.

How common is MYLK p.Ala1826Val (c.5477C>T) in the general population?

MYLK p.Ala1826Val (c.5477C>T) is ultra-rare (popmax 0.0987%, mid) (gnomAD).

What do computational predictors say about MYLK p.Ala1826Val (c.5477C>T)?

AlphaMissense predicts ambiguous (score 0.3611) — an in-silico prediction, not a clinical call.

MYLK p.Ala1826Val

Q: What condition is associated with MYLK p.Ala1826Val (c.5477C>T)?

MYLK p.Ala1826Val (c.5477C>T) is associated with familial thoracic aortic aneurysm and aortic dissection, aortic aneurysm, familial thoracic 7 (ClinVar).

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.5477C>T · rs147187907 · VCV252775

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

ambiguous

0.3611 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0987%, mid)

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.3611	ambiguous
REVEL	0.342	indeterminate
SaProt	LLR -7.61	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 50 kb · p 2.5e-20 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0987% Middle Eastern · 6/6,080 alleles

Filtering AF 0.0701% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0684%

Overall 0.059% 953/1,613,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0987%	1,013
European (non-Finnish)	0.0742%	1,349
Remaining individualsnot 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
Finnishnot grpmax-eligible	0.00469%	21,337

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MYLK
Protein: p.Ala1826Val
Coding: c.5477C>T
MANE Select: NM_053025
dbSNP: rs147187907
Type: single nucleotide variant
Location: chr3:123618662 (GRCh38)
Gene constraint: LOEUF 0.604 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.54 · 8 PDB
Residue 1826: a UniProt-annotated variant site (in aat7; uncertain significance); the ig-like c2-type 9 domain

Full MYLK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: aortic aneurysm, familial thoracic 7

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

MYLK c.2390+1G>A Likely pathogenic ★★ same condition
MYLK p.Arg1275Ter Pathogenic ★★ same condition
MYLK p.Arg1480Ter Pathogenic/Likely pathogenic ★★ same condition
MYLK c.1310-1G>A Uncertain significance ★★ same condition
MYLK c.1652-2A>C Uncertain significance ★★ same condition
MYLK c.1804+5G>T Uncertain significance ★★ same condition
MYLK c.2140+5G>C Uncertain significance ★★ same condition
MYLK c.2462+3G>A Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mylk-p-ala1826val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown