Is MYO7A p.Arg649Gln (c.1946G>A) pathogenic?

MYO7A p.Arg649Gln (c.1946G>A) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-03). AlphaMissense: likely pathogenic (0.6136); Very rare (popmax 0.00454%, sas); Associated with autosomal recessive nonsyndromic hearing loss 2.

What condition is associated with MYO7A p.Arg649Gln (c.1946G>A)?

MYO7A p.Arg649Gln (c.1946G>A) is associated with autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Arg649Gln (c.1946G>A) in the general population?

MYO7A p.Arg649Gln (c.1946G>A) is very rare (popmax 0.00454%, sas) (gnomAD).

What do computational predictors say about MYO7A p.Arg649Gln (c.1946G>A)?

AlphaMissense predicts likely pathogenic (score 0.6136) — an in-silico prediction, not a clinical call.

MYO7A p.Arg649Gln

c.1946G>A · rs1308203959 · VCV1185144

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6136 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00454%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 2

Computational evidence

Protein change
AlphaMissense	0.6136	likely pathogenic
REVEL	0.787	moderately pathogenic-leaning
SaProt	LLR -6.21	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 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	25.1	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 0.00454% South Asian · 4/88,042 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000915%

Overall 0.00132% 21/1,594,538 alleles · very rare exomes 19/1,442,314 · genomes 2/152,224 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00454%	22,010
African / African-American	0.00268%	37,260
European (non-Finnish)	0.00128%	78,084

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.Arg649Gln
Coding: c.1946G>A
MANE Select: NM_000260
dbSNP: rs1308203959
Type: single nucleotide variant
Location: chr11:77174766 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 649: the myosin motor domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MYO7A p.Arg649Trp Uncertain significance ★★ ⚠ same residue
MYO7A p.Arg649= Likely benign ★ same residue
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
MYO7A p.Glu968Asp 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-arg649gln (accessed [today's date]).

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