Is MYO7A p.His133fs (c.397dup) pathogenic?

MYO7A p.His133fs (c.397dup) is classified Pathogenic in MYO7A (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-08). Very rare (popmax 0.00446%, eas); Associated with MYO7A-related disorder.

What condition is associated with MYO7A p.His133fs (c.397dup)?

MYO7A p.His133fs (c.397dup) is associated with MYO7A-related disorder, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.His133fs (c.397dup) in the general population?

MYO7A p.His133fs (c.397dup) is very rare (popmax 0.00446%, eas) (gnomAD).

MYO7A p.His133fs

c.397dup · rs111033187 · VCV43229

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

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 5 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, 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 0.00446% East Asian · 2/44,888 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00174% 28/1,613,250 alleles · very rare exomes 25/1,461,192 · genomes 3/152,058 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,818
Finnishnot grpmax-eligible	0.00471%	21,224
East Asiangrpmax	0.00446%	22,444
European (non-Finnish)	0.00161%	62,095
African / African-American	0.00134%	74,872

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.His133fs
Coding: c.397dup
MANE Select: NM_000260
dbSNP: rs111033187
Type: Duplication
Location: chr11:77156011 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 133: the myosin motor domain; a UniProt-annotated variant site (in ush1b; uncertain significance)

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

Disease context

MYO7A-related disorder

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

Similar variants

MYO7A p.His133Asn Likely pathogenic ★★★ same residue
MYO7A p.His133Tyr Pathogenic/Likely pathogenic ★★ same residue
MYO7A p.His133Asp Pathogenic ★ same residue
MYO7A p.Asp365fs Pathogenic ★★ same condition
MYO7A p.Glu1830fs Likely pathogenic ★★ same condition
MYO7A p.Gly1842fs Pathogenic ★★ same condition
MYO7A p.Ile454fs Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Ile94fs 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-his133fs (accessed [today's date]).

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