Is MYO7A p.Lys420Ter (c.1258A>T) pathogenic?

MYO7A p.Lys420Ter (c.1258A>T) is classified Pathogenic in MYO7A (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-04-02). Ultra-rare (popmax 0.0165%, mid); Associated with Monogenic hearing loss.

What condition is associated with MYO7A p.Lys420Ter (c.1258A>T)?

MYO7A p.Lys420Ter (c.1258A>T) is associated with Monogenic hearing loss, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Lys420Ter (c.1258A>T) in the general population?

MYO7A p.Lys420Ter (c.1258A>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

MYO7A p.Lys420Ter

c.1258A>T · rs782539587 · VCV504508

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Monogenic hearing loss

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 49
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Overall
CADD	41.0	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.000868% 14/1,613,518 alleles · ultra-rare exomes 14/1,461,390 · genomes 0/152,128 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
South Asian	0.0088%	11,368
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.000339%	294,936

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.Lys420Ter
Coding: c.1258A>T
MANE Select: NM_000260
dbSNP: rs782539587
Type: single nucleotide variant
Location: chr11:77161030 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 420: the myosin motor domain

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

Disease context

Monogenic hearing loss

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

Similar variants

MYO7A p.Lys420Glu Uncertain significance ⚠ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same condition
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same condition
MYO7A p.Arg668Cys Pathogenic ★★★ same condition
MYO7A p.Arg853His Likely pathogenic ★★★ same condition
MYO7A p.Glu968Asp 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-lys420ter (accessed [today's date]).

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