Is MYO7A p.Asn458Lys (c.1374T>G) pathogenic?

MYO7A p.Asn458Lys (c.1374T>G) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-08). AlphaMissense: likely pathogenic (0.9992); Very rare (popmax 0.0017%, amr).

How common is MYO7A p.Asn458Lys (c.1374T>G) in the general population?

MYO7A p.Asn458Lys (c.1374T>G) is very rare (popmax 0.0017%, amr) (gnomAD).

What do computational predictors say about MYO7A p.Asn458Lys (c.1374T>G)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

MYO7A p.Asn458Lys

c.1374T>G · rs782293740 · VCV504950

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic · top 1% in MYO7A
REVEL	0.658	pathogenic-leaning
SaProt	LLR -11.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -13	GERP -3.8
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	7.399	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0017% Admixed American · 1/58,752 alleles

Overall 6.23e-05% 1/1,603,898 alleles · very rare exomes 1/1,451,568 · genomes 0/152,330 · 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.Asn458Lys
Coding: c.1374T>G
MANE Select: NM_000260
dbSNP: rs782293740
Type: single nucleotide variant
Location: chr11:77162150 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 458: the myosin motor domain; a UniProt-annotated variant site (in dfna11)

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

Similar variants

MYO7A p.Asn458Ser Uncertain significance ★★ ⚠ same residue
MYO7A p.Asn458Asp Likely pathogenic ★ same residue
MYO7A p.Asn458Ile Pathogenic ★ same residue
MYO7A p.Asn458= Likely benign ★ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same type
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same type
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same type
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same type

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-asn458lys (accessed [today's date]).

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