Is MYO7A p.Arg395Cys (c.1183C>T) pathogenic?

MYO7A p.Arg395Cys (c.1183C>T) is classified Likely pathogenic in MYO7A (ClinVar, Expert panel, 7 submitters; last evaluated 2024-09-24). AlphaMissense: likely pathogenic (0.8026); Very rare (popmax 0.00471%, sas); Associated with nonsyndromic genetic hearing loss.

What condition is associated with MYO7A p.Arg395Cys (c.1183C>T)?

MYO7A p.Arg395Cys (c.1183C>T) is associated with nonsyndromic genetic hearing loss, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Arg395Cys (c.1183C>T) in the general population?

MYO7A p.Arg395Cys (c.1183C>T) is very rare (popmax 0.00471%, sas) (gnomAD).

How is Rare non-syndromic genetic deafness inherited?

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

What do computational predictors say about MYO7A p.Arg395Cys (c.1183C>T)?

AlphaMissense predicts likely pathogenic (score 0.8026) — an in-silico prediction, not a clinical call.

MYO7A p.Arg395Cys

c.1183C>T · rs782279338 · VCV555138

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.8026 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00471%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nonsyndromic genetic hearing loss

ClinGen expert panel — Hearing Loss VCEP

Likely Pathogenic for nonsyndromic genetic deafness. Applied ACMG criteria (verbatim):

PP1_Strong PP3 PM3

Curation rationale (ClinGen, verbatim)

The c.1183C>T variant in MYO7A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 395. The highest population minor allele frequency in gnomAD v4.1 is 0.00008472 (2/23608 alleles) in the South Asian population. (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.773, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 6 individuals with nonsyndromic genetic hearing loss. Out of 3 of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant for Usher syndrome and none of those were confirmed in trans (c.401T>A (p.Ile134Asn), 0 PM3 points, SCV: SCV001232108.5, Invitae). The other 2 were compound heterozygous for the variant and a variant of uncertain significance for nonsyndromic genetic hearing loss, 1 of them was confirmed in trans by family testing (0.25 PM3 points, c.1496T>C (p.Ile499Thr); c.1496T>C(p.Ile499Thr), PMIDs: 34416374, 34979615). 3 individuals were homozygous for the variant (1 PM3 point, PMIDs: 23770805, 27573290, ClinVar SCV: SCV001232108.5, Invitae) (PM3). The variant has been reported to segregate with nonsyndromic genetic hearing loss in 8 affected family members from 3 families (PP1_Strong; PMIDs: 23770805, 27573290, 34979615). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_Strong, PM3, PP3. (ClinGen Hearing Loss VCEP specifications version 2; 7/23/2024)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.8026	likely pathogenic ✓ concordant with ClinVar
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -9.86	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.66	GERP -2.1, phastCons 0.098
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	29.1	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 0.00471% South Asian · 4/84,970 alleles

Filtering AF 0.0016% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000941%

Overall 0.00115% 18/1,568,648 alleles · very rare exomes 18/1,416,370 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00471%	21,243
Admixed American	0.00372%	26,887
Remaining individualsnot grpmax-eligible	0.00164%	60,892
European (non-Finnish)	0.00095%	105,231

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.Arg395Cys
Coding: c.1183C>T
MANE Select: NM_000260
dbSNP: rs782279338
Type: single nucleotide variant
Location: chr11:77160265 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 395: the myosin motor domain

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

Disease context

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

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

For Rare non-syndromic genetic deafness (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

MYO7A p.Arg395His Pathogenic/Likely pathogenic ★★ same residue
MYO7A p.Arg395= 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.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-arg395cys (accessed [today's date]).

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