Is MYO7A p.Lys515Asn (c.1545G>T) pathogenic?

MYO7A p.Lys515Asn (c.1545G>T) is classified Conflicting classifications of pathogenicity in MYO7A (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-04-02). AlphaMissense: likely pathogenic (0.9546); Very rare (popmax 0.00253%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 2.

What condition is associated with MYO7A p.Lys515Asn (c.1545G>T)?

MYO7A p.Lys515Asn (c.1545G>T) is associated with autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Lys515Asn (c.1545G>T) in the general population?

MYO7A p.Lys515Asn (c.1545G>T) is very rare (popmax 0.00253%, nfe) (gnomAD).

What do computational predictors say about MYO7A p.Lys515Asn (c.1545G>T)?

AlphaMissense predicts likely pathogenic (score 0.9546) — an in-silico prediction, not a clinical call.

MYO7A p.Lys515Asn

c.1545G>T · rs782313585 · VCV1675469

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9546 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00253%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 2

Computational evidence

Protein change
AlphaMissense	0.9546	likely pathogenic
REVEL	0.25	benign-leaning
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.5	GERP -1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00253% European (non-Finnish) · 29/1,147,050 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00153%

Overall 0.002% 31/1,551,472 alleles · very rare exomes 29/1,399,274 · genomes 2/152,198 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00333%	30,041
European (non-Finnish)grpmax	0.00253%	39,554

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.Lys515Asn
Coding: c.1545G>T
MANE Select: NM_000260
dbSNP: rs782313585
Type: single nucleotide variant
Location: chr11:77162321 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 515: the myosin motor domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MYO7A p.Lys515Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MYO7A p.Lys515= Likely benign ★ same residue
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-lys515asn (accessed [today's date]).

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