Is MYO7A p.Arg1164Gln (c.3491G>A) pathogenic?

MYO7A p.Arg1164Gln (c.3491G>A) is classified Uncertain significance in MYO7A (ClinVar, Expert panel, 7 submitters; last evaluated 2024-03-28). AlphaMissense: likely pathogenic (0.9414); Very rare (popmax 0.00448%, sas); Associated with Usher syndrome.

What condition is associated with MYO7A p.Arg1164Gln (c.3491G>A)?

MYO7A p.Arg1164Gln (c.3491G>A) is associated with Usher syndrome, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Arg1164Gln (c.3491G>A) in the general population?

MYO7A p.Arg1164Gln (c.3491G>A) is very rare (popmax 0.00448%, sas) (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.Arg1164Gln (c.3491G>A)?

AlphaMissense predicts likely pathogenic (score 0.9414) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1164Gln

c.3491G>A · rs782350886 · VCV229012

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9414 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00448%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome

ClinGen expert panel — Hearing Loss VCEP

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

PM2_Supporting PP3

Curation rationale (ClinGen, verbatim)

The c.3491G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1164 (p.Arg1164Gln). The highest population filtering allele frequency with a confidence interval of 0.95 in gnomAD v4 is 0.00001446 (4/89272 alleles) in the South Asian population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.935, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3. (ClinGen Hearing Loss VCEP specifications version 2, 01.17.2024)

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

Computational evidence

Protein change
AlphaMissense	0.9414	likely pathogenic
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -7.77	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.4, 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 0.00448% South Asian · 4/89,272 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000905%

Overall 0.00131% 21/1,600,224 alleles · very rare exomes 19/1,448,048 · genomes 2/152,176 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00642%	15,578
South Asiangrpmax	0.00448%	22,318
Admixed American	0.00173%	57,964
European (non-Finnish)	0.00102%	97,760

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1164Gln
Coding: c.3491G>A
MANE Select: NM_000260
dbSNP: rs782350886
Type: single nucleotide variant
Location: chr11:77184703 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1164: the myth4 1 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.Arg1164Trp Uncertain significance ★★ ⚠ same residue
MYO7A p.Arg1164= 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
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-arg1164gln (accessed [today's date]).

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