Is MYO7A p.Arg1749Gln (c.5246G>A) pathogenic?

MYO7A p.Arg1749Gln (c.5246G>A) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-12-15). AlphaMissense: ambiguous (0.3821); Ultra-rare (popmax 0.0122%, eas); Associated with hearing loss, autosomal dominant 80.

What condition is associated with MYO7A p.Arg1749Gln (c.5246G>A)?

MYO7A p.Arg1749Gln (c.5246G>A) is associated with hearing loss, autosomal dominant 80, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Arg1749Gln (c.5246G>A) in the general population?

MYO7A p.Arg1749Gln (c.5246G>A) is ultra-rare (popmax 0.0122%, eas) (gnomAD).

What do computational predictors say about MYO7A p.Arg1749Gln (c.5246G>A)?

AlphaMissense predicts ambiguous (score 0.3821) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1749Gln

c.5246G>A · rs781537330 · VCV229007

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.3821 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, eas)

Conditions

hearing loss, autosomal dominant 80

Computational evidence

Protein change
AlphaMissense	0.3821	ambiguous
REVEL	0.418	indeterminate
SaProt	LLR -8.17	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP -0.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	26.7	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 0.0122% East Asian · 5/41,056 alleles

Filtering AF 0.00874% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00817%

Overall 0.00832% 129/1,550,640 alleles · ultra-rare exomes 122/1,398,402 · genomes 7/152,238 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0122%	8,211
European (non-Finnish)	0.0103%	9,728
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,670
Remaining individualsnot grpmax-eligible	0.00333%	29,996
African / African-American	0.00274%	36,541
Admixed American	0.00195%	51,162

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.Arg1749Gln
Coding: c.5246G>A
MANE Select: NM_000260
dbSNP: rs781537330
Type: single nucleotide variant
Location: chr11:77203137 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1749: the myth4 2 domain

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

Disease context

hearing loss, autosomal dominant 80 — 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

Similar variants

MYO7A p.Arg1749Trp Uncertain significance ★★ ⚠ same residue
MYO7A p.Arg1749= 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-arg1749gln (accessed [today's date]).

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