Is MYO7A p.Arg668Cys (c.2002C>T) pathogenic?

MYO7A p.Arg668Cys (c.2002C>T) is classified Pathogenic in MYO7A (ClinVar, Expert panel, 10 submitters; last evaluated 2026-05-20). AlphaMissense: likely pathogenic (0.986); Very rare (popmax 0.00667%, afr); Associated with Usher syndrome.

What condition is associated with MYO7A p.Arg668Cys (c.2002C>T)?

MYO7A p.Arg668Cys (c.2002C>T) is associated with Usher syndrome, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Arg668Cys (c.2002C>T) in the general population?

MYO7A p.Arg668Cys (c.2002C>T) is very rare (popmax 0.00667%, 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.Arg668Cys (c.2002C>T)?

AlphaMissense predicts likely pathogenic (score 0.986) — an in-silico prediction, not a clinical call.

MYO7A p.Arg668Cys

c.2002C>T · rs397516292 · VCV43168

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome

ClinGen expert panel — Hearing Loss VCEP

Pathogenic for Usher syndrome. Applied ACMG criteria (verbatim):

PM3_VeryStrong PP3 PP4

Curation rationale (ClinGen, verbatim)

The c.2002C>T variant in MYO7A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 668. The highest population minor allele frequency in gnomAD v4.1 is 0.00003344 (48/1179790 alleles) in the European non-finnish population, ( PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.794, which is above the threshold of 0.7, evidence that correlates with impact on MYO7A function (PP3 met). This variant has been detected in 3 individuals with usher syndrome and 1 with sensorineural hearing loss. All of those individuals, were compound heterozygous for the variant and a pathogenic variant and 3 of those were confirmed in trans by parental testing (PM3_VeryStrong, PP4; PMID: 20146813, 26969326, SCV001397007.7, Labcorp Genetics internal data). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PP4, PP3. (ClinGen Hearing Loss VCEP specifications version 2; 05/20/2026).

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

Computational evidence

Protein change
AlphaMissense	0.986	likely pathogenic ✓ concordant with ClinVar
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -14.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, 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 0.00667% African / African-American · 5/74,940 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00353% 57/1,613,186 alleles · very rare exomes 54/1,460,964 · genomes 3/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,988
Remaining individualsnot grpmax-eligible	0.00641%	15,610
European (non-Finnish)	0.00407%	24,579

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.Arg668Cys
Coding: c.2002C>T
MANE Select: NM_000260
dbSNP: rs397516292
Type: single nucleotide variant
Location: chr11:77174822 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 668: 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 autosomal dominant nonsyndromic hearing loss 11 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.Arg668His Conflicting classifications of pathogenicity ★ ⚠ same residue
MYO7A p.Arg668Leu Uncertain significance ★ ⚠ same residue
MYO7A p.Arg668Pro Likely pathogenic ★ 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.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-arg668cys (accessed [today's date]).

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