Is MYO7A p.Met1517fs (c.4550_4551del) pathogenic?

MYO7A p.Met1517fs (c.45504551del) is classified Pathogenic in MYO7A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-12). Very rare (popmax 0.00133%, afr); Associated with MYO7A-related disorder.

What condition is associated with MYO7A p.Met1517fs (c.4550_4551del)?

MYO7A p.Met1517fs (c.4550_4551del) is associated with MYO7A-related disorder (ClinVar).

How common is MYO7A p.Met1517fs (c.4550_4551del) in the general population?

MYO7A p.Met1517fs (c.4550_4551del) is very rare (popmax 0.00133%, afr) (gnomAD).

MYO7A p.Met1517fs

c.4550_4551del · VCV4802462

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

MYO7A-related disorder

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 34 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.9	GERP 0.72, phastCons 1
Overall
CADD	35.0	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 0.00133% African / African-American · 1/74,928 alleles

Overall 0.000124% 2/1,613,754 alleles · very rare exomes 1/1,461,556 · genomes 1/152,198 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,464
African / African-Americangrpmax	0.00133%	74,928

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: MYO7A
Protein: p.Met1517fs
Coding: c.4550_4551del
MANE Select: NM_000260
Type: Deletion
Location: chr11:77198603 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1517: the ferm 1 domain

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

Disease context

MYO7A-related disorder

Similar variants

MYO7A p.Ala1277fs Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Ala2009fs Pathogenic ★★ same condition
MYO7A p.Asn769fs Pathogenic ★★ same condition
MYO7A p.Asp521fs Pathogenic ★★ same condition
MYO7A p.Gln1395fs Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Gln2066fs Pathogenic ★★ same condition
MYO7A p.Glu166fs Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Gly1547_Leu1548insTer Pathogenic/Likely 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-met1517fs (accessed [today's date]).

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