Is MYO7A p.Arg378Cys (c.1132C>T) pathogenic?

MYO7A p.Arg378Cys (c.1132C>T) is classified Conflicting classifications of pathogenicity in MYO7A (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2024-11-25). AlphaMissense: likely pathogenic (0.8922); Ultra-rare (popmax 0.0295%, nfe); Associated with Usher syndrome type 1.

What condition is associated with MYO7A p.Arg378Cys (c.1132C>T)?

MYO7A p.Arg378Cys (c.1132C>T) is associated with Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2, autosomal dominant nonsyndromic hearing loss 11 (ClinVar).

How common is MYO7A p.Arg378Cys (c.1132C>T) in the general population?

MYO7A p.Arg378Cys (c.1132C>T) is ultra-rare (popmax 0.0295%, nfe) (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.Arg378Cys (c.1132C>T)?

AlphaMissense predicts likely pathogenic (score 0.8922) — an in-silico prediction, not a clinical call.

MYO7A p.Arg378Cys

c.1132C>T · rs199818783 · VCV43135

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.8922 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0295%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.8922	likely pathogenic
REVEL	0.731	pathogenic-leaning
SaProt	LLR -12.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	32.0	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 0.0295% European (non-Finnish) · 343/1,164,244 alleles

Filtering AF 0.0269% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.0276% 436/1,581,022 alleles · ultra-rare exomes 405/1,428,842 · genomes 31/152,180 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0784%	1,276
Remaining individualsnot grpmax-eligible	0.0441%	2,269
European (non-Finnish)grpmax	0.0295%	3,394
Admixed American	0.0198%	5,063
African / African-American	0.0054%	18,521
South Asian	0.00349%	28,627

Finnish 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.Arg378Cys
Coding: c.1132C>T
MANE Select: NM_000260
dbSNP: rs199818783
Type: single nucleotide variant
Location: chr11:77160214 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 378: 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 autosomal dominant nonsyndromic hearing loss 11 inherited retinal dystrophy Usher syndrome type 1B

For Usher syndrome (Orphanet):

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

Similar variants

MYO7A p.Arg378His Uncertain significance ★★ ⚠ same residue
MYO7A p.Arg378Leu Uncertain significance ★ ⚠ same residue
MYO7A p.Arg378Pro Uncertain significance ★ ⚠ same residue
MYO7A p.Arg378= 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

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-arg378cys (accessed [today's date]).

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