Is MYO7A p.Ser1666Cys (c.4996A>T) pathogenic?

MYO7A p.Ser1666Cys (c.4996A>T) is classified Benign/Likely benign in MYO7A (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0418); Common (popmax 68.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Usher syndrome type 1.

What condition is associated with MYO7A p.Ser1666Cys (c.4996A>T)?

MYO7A p.Ser1666Cys (c.4996A>T) is associated with Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2, autosomal dominant nonsyndromic hearing loss 11 (ClinVar).

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.Ser1666Cys (c.4996A>T)?

AlphaMissense predicts likely benign (score 0.0418) — an in-silico prediction, not a clinical call.

MYO7A p.Ser1666Cys

Q: How common is MYO7A p.Ser1666Cys (c.4996A>T) in the general population?

MYO7A p.Ser1666Cys (c.4996A>T) is common (popmax 68.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4996A>T · rs2276288 · VCV43269

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0418 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 68.6%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0418	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -5.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.48 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.2	GERP 0.41, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	16.56	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 68.6% African / African-American · 51,430/74,954 alleles

Filtering AF 68.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 67.9%

Overall 54.8% 884,636/1,613,536 alleles · common exomes 795,340/1,461,568 · genomes 89,296/151,968 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	68.6%	1
Admixed American	65.5%	2
Finnishnot grpmax-eligible	62.5%	2
European (non-Finnish)	55.1%	2
Remaining individualsnot grpmax-eligible	53.1%	2
Amishnot grpmax-eligible	48.7%	2
East Asian	47.2%	2
Middle Eastern	44.8%	2
Ashkenazi Jewishnot grpmax-eligible	43.5%	2
South Asian	37%	3

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.Ser1666Cys
Coding: c.4996A>T
MANE Select: NM_000260
dbSNP: rs2276288
Type: single nucleotide variant
Location: chr11:77201591 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1666: a UniProt-annotated variant site (in); a UniProt-annotated variant site (sequence variant); the sh3 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 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.Ser1666Thr Uncertain significance ⚠ same residue
MYO7A p.Ser1666fs Pathogenic ★ same residue
MYO7A p.Ser1666Ile Uncertain significance ★★ ⚠ 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-ser1666cys (accessed [today's date]).

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