Is MYO7A p.Gly1159Ser (c.3475G>A) pathogenic?

MYO7A p.Gly1159Ser (c.3475G>A) is classified Conflicting classifications of pathogenicity in MYO7A (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-03-24). AlphaMissense: likely pathogenic (0.9872); Ultra-rare (popmax 0.0293%, eas); Associated with Usher syndrome type 1.

What condition is associated with MYO7A p.Gly1159Ser (c.3475G>A)?

MYO7A p.Gly1159Ser (c.3475G>A) is associated with Usher syndrome type 1, retinal disorder, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Gly1159Ser (c.3475G>A) in the general population?

MYO7A p.Gly1159Ser (c.3475G>A) is ultra-rare (popmax 0.0293%, eas) (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.Gly1159Ser (c.3475G>A)?

AlphaMissense predicts likely pathogenic (score 0.9872) — an in-silico prediction, not a clinical call.

MYO7A p.Gly1159Ser

c.3475G>A · rs568495838 · VCV1306607

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9872 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.9872	likely pathogenic
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -9.07	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 9.7	GERP 0.39, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	31.0	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 0.0293% East Asian · 13/44,432 alleles

Filtering AF 0.0173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00306% 49/1,599,560 alleles · ultra-rare exomes 47/1,447,214 · genomes 2/152,346 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0293%	3,418
South Asian	0.00562%	17,807
Admixed American	0.00345%	28,956
Remaining individualsnot grpmax-eligible	0.00323%	30,968
European (non-Finnish)	0.0023%	43,436

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.Gly1159Ser
Coding: c.3475G>A
MANE Select: NM_000260
dbSNP: rs568495838
Type: single nucleotide variant
Location: chr11:77184687 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1159: the myth4 1 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: retinal disorder 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.Gly1159Val Pathogenic/Likely pathogenic ★★ same residue
MYO7A p.Gly1159Arg 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
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-gly1159ser (accessed [today's date]).

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