Is MYO7A p.Arg666Gln (c.1997G>A) pathogenic?

MYO7A p.Arg666Gln (c.1997G>A) is classified Uncertain significance in MYO7A (ClinVar, Expert panel, 8 submitters; last evaluated 2025-03-12). AlphaMissense: ambiguous (0.4053); Ultra-rare (popmax 0.0187%, afr); Associated with Usher syndrome.

What condition is associated with MYO7A p.Arg666Gln (c.1997G>A)?

MYO7A p.Arg666Gln (c.1997G>A) is associated with Usher syndrome, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Arg666Gln (c.1997G>A) in the general population?

MYO7A p.Arg666Gln (c.1997G>A) is ultra-rare (popmax 0.0187%, afr) (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.Arg666Gln (c.1997G>A)?

AlphaMissense predicts ambiguous (score 0.4053) — an in-silico prediction, not a clinical call.

MYO7A p.Arg666Gln

c.1997G>A · rs782396605 · VCV556881

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.4053 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Usher syndrome

ClinGen expert panel — Hearing Loss VCEP

Uncertain Significance for Usher syndrome. Applied ACMG criteria (verbatim):

PP3

Curation rationale (ClinGen, verbatim)

The c.1997G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by glycine at amino acid 666. The highest population minor allele frequency in gnomAD v4.1 is 0.0001865 (14/75048 alleles) in the African/African-American population (PM2_Supporting and BS1_Supporting are not met). The computational predictor REVEL gives a score of 0.841, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been observed in one proband with Usher syndrome, four probands with hearing loss, and two probands with retinal disease. However, they all harbored another variant of uncertain significance c.3527G>A (p.Ser1176Asn) with phase unknown, and two who were found to have an alternate molecular basis for disease (PM3_Supporting not met; ClinVar ID: 196099; PMIDs: 27460420, 31479088, 33297549, 27344577, LabCorp Genetics (formerly Invitae) internal data ClinVar SCV001498602.2, GeneDx internal data). In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3 (ClinGen Hearing Loss VCEP specifications version 2; 3/12/2025).

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

Computational evidence

Protein change
AlphaMissense	0.4053	ambiguous
REVEL	0.841	moderately pathogenic-leaning
SaProt	LLR -11.66	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP -0.41, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	29.3	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 0.0187% African / African-American · 14/75,048 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00903%

Overall 0.00161% 26/1,613,040 alleles · ultra-rare exomes 13/1,460,678 · genomes 13/152,362 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,361
Remaining individualsnot grpmax-eligible	0.00801%	12,491
Admixed American	0.00167%	59,944
European (non-Finnish)	0.000509%	196,616

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.Arg666Gln
Coding: c.1997G>A
MANE Select: NM_000260
dbSNP: rs782396605
Type: single nucleotide variant
Location: chr11:77174817 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 666: the myosin motor domain

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

Disease context

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

Also linked: Usher syndrome type 1 autosomal recessive nonsyndromic hearing loss 2 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.Arg666Ter Pathogenic ★★ same residue
MYO7A p.Arg666Pro Pathogenic ★ same residue
MYO7A p.Arg666= 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

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-arg666gln (accessed [today's date]).

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