Is MYO7A p.Phe1346del (c.4033TTC[1]) pathogenic?

MYO7A p.Phe1346del (c.4033TTC[1]) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-11). Very rare (popmax 0.000254%, nfe); Associated with autosomal dominant nonsyndromic hearing loss 11.

What condition is associated with MYO7A p.Phe1346del (c.4033TTC[1])?

MYO7A p.Phe1346del (c.4033TTC[1]) is associated with autosomal dominant nonsyndromic hearing loss 11, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Phe1346del (c.4033TTC[1]) in the general population?

MYO7A p.Phe1346del (c.4033TTC[1]) is very rare (popmax 0.000254%, nfe) (gnomAD).

MYO7A p.Phe1346del

c.4033TTC[1] · rs1437625274 · VCV557280

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

autosomal dominant nonsyndromic hearing loss 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.9	GERP 0.53, phastCons 1
Overall
CADD	19.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,912 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,908 alleles · very rare exomes 2/1,461,636 · genomes 1/152,272 · joint denominator

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.Phe1346del
Coding: c.4033TTC[1]
MANE Select: NM_000260
dbSNP: rs1437625274
Type: Microsatellite
Location: chr11:77192157 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1346: a UniProt-annotated variant site (in ush1b); the ferm 1 domain

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

Disease context

autosomal dominant nonsyndromic hearing loss 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

MYO7A p.Glu1716del Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Leu1293fs Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Lys923del Likely pathogenic ★★ same condition
MYO7A p.Phe1963del Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Ser423fs Likely pathogenic ★★ same condition
MYO7A p.Trp47fs Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Val1501fs Pathogenic/Likely pathogenic ★★ same condition
MYO7A p.Arg1448del 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/myo7a-p-phe1346del (accessed [today's date]).

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