Is MYO7A p.Lys542fs (c.1623dup) pathogenic?

MYO7A p.Lys542fs (c.1623dup) is classified Pathogenic in MYO7A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-31). Very rare (popmax 0.005%, nfe); Associated with Usher syndrome type 1.

What condition is associated with MYO7A p.Lys542fs (c.1623dup)?

MYO7A p.Lys542fs (c.1623dup) is associated with Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2, autosomal dominant nonsyndromic hearing loss 11 (ClinVar).

How common is MYO7A p.Lys542fs (c.1623dup) in the general population?

MYO7A p.Lys542fs (c.1623dup) is very rare (popmax 0.005%, nfe) (gnomAD).

How is Usher syndrome inherited?

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

MYO7A p.Lys542fs

c.1623dup · rs782077721 · VCV521129

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.005%, nfe)

Conditions

Usher syndrome type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% European (non-Finnish) · 59/1,179,574 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00397% 64/1,612,458 alleles · very rare exomes 61/1,461,600 · genomes 3/150,858 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.005%	19,993
East Asian	0.00223%	44,832
South Asian	0.0022%	45,489
Remaining individualsnot grpmax-eligible	0.0016%	62,456
African / African-American	0.00134%	74,460

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: MYO7A
Protein: p.Lys542fs
Coding: c.1623dup
MANE Select: NM_000260
dbSNP: rs782077721
Type: Duplication
Location: chr11:77162914 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 542: the myosin motor domain

Full MYO7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Usher syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 2 autosomal dominant nonsyndromic hearing loss 11 Usher syndrome type 1B

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

MYO7A p.Asp365fs Pathogenic ★★ same condition
MYO7A p.Glu1830fs Likely pathogenic ★★ same condition
MYO7A p.Gly1842fs Pathogenic ★★ same condition
MYO7A p.His133fs Pathogenic ★★ same condition
MYO7A p.Ile454fs Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Ile94fs Likely pathogenic ★★ same condition
MYO7A p.Leu1046fs Pathogenic ★★ same condition
MYO7A p.Lys2078fs Pathogenic ★★ 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/myo7a-p-lys542fs (accessed [today's date]).

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