Is MYO7A p.Leu375Val (c.1123C>G) pathogenic?

MYO7A p.Leu375Val (c.1123C>G) is classified Uncertain significance in MYO7A (ClinVar, Single submitter, 2 submitters; last evaluated 2013-12-05). AlphaMissense: likely benign (0.1855); Ultra-rare (popmax 0.0221%, sas); Associated with Usher syndrome type 1.

What condition is associated with MYO7A p.Leu375Val (c.1123C>G)?

MYO7A p.Leu375Val (c.1123C>G) is associated with Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Leu375Val (c.1123C>G) in the general population?

MYO7A p.Leu375Val (c.1123C>G) is ultra-rare (popmax 0.0221%, sas) (gnomAD).

How is Usher syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MYO7A p.Leu375Val (c.1123C>G)?

AlphaMissense predicts likely benign (score 0.1855) — an in-silico prediction, not a clinical call.

MYO7A p.Leu375Val

c.1123C>G · rs782728522 · VCV164666

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1855 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0221%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.1855	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.85	GERP -3.2, phastCons 0.98
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0221% South Asian · 19/85,814 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.012%

Overall 0.00127% 20/1,580,244 alleles · ultra-rare exomes 18/1,428,028 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0221%	4,517
Middle Eastern	0.0168%	5,966

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.Leu375Val
Coding: c.1123C>G
MANE Select: NM_000260
dbSNP: rs782728522
Type: single nucleotide variant
Location: chr11:77160205 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 375: the myosin motor domain

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

Disease context

Usher syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 2

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

MYO7A p.Leu375Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
MYO7A p.Leu375= Likely benign ★ 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

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-leu375val (accessed [today's date]).

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