Is MYOT p.Val431Met (c.1291G>A) pathogenic?

MYOT p.Val431Met (c.1291G>A) is classified Uncertain significance in MYOT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-05). AlphaMissense: likely benign (0.2485); Very rare (popmax 0.00267%, afr); Associated with myofibrillar myopathy 3.

What condition is associated with MYOT p.Val431Met (c.1291G>A)?

MYOT p.Val431Met (c.1291G>A) is associated with myofibrillar myopathy 3 (ClinVar).

How common is MYOT p.Val431Met (c.1291G>A) in the general population?

MYOT p.Val431Met (c.1291G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Distal myotilinopathy inherited?

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

What do computational predictors say about MYOT p.Val431Met (c.1291G>A)?

AlphaMissense predicts likely benign (score 0.2485) — an in-silico prediction, not a clinical call.

MYOT p.Val431Met

c.1291G>A · rs756306645 · VCV1021569

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2485 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

myofibrillar myopathy 3

Computational evidence

Protein change
AlphaMissense	0.2485	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	—	withheld · numbering disagrees past residue 74 · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 17 kb · p 0.00034 · regional, not allelic
Overall
CADD	19.94	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,028 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,613,564 alleles · very rare exomes 4/1,461,256 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,245
African / African-Americangrpmax	0.00267%	37,514

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

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: MYOT
Protein: p.Val431Met
Coding: c.1291G>A
MANE Select: NM_006790
dbSNP: rs756306645
Type: single nucleotide variant
Location: chr5:137886964 (GRCh38)
Gene constraint: LOEUF 0.923 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.17 · 2 PDB
Residue 431: the ig-like c2-type 2 domain; a β-strand; the 'necessary for interaction with acta1' region; the 'necessary for interaction with flnc' region

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

Disease context

myofibrillar myopathy 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Distal myotilinopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MYOT p.Ser55Phe Pathogenic/Likely pathogenic ★★ ⚠ same condition
MYOT p.Ser60Cys Pathogenic ★★ ⚠ same condition
MYOT p.Ser60Phe Pathogenic/Likely pathogenic ★★ same condition
MYOT c.531+4G>C Uncertain significance ★★ same condition
MYOT p.Ala131Glu Uncertain significance ★★ ⚠ same condition
MYOT p.Ala137Thr Uncertain significance ★★ ⚠ same condition
MYOT p.Ala218Val Uncertain significance ★★ ⚠ same condition
MYOT p.Arg178Cys 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/myot-p-val431met (accessed [today's date]).

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