Is MYO7A p.Arg1146Gln (c.3437G>A) pathogenic?

MYO7A p.Arg1146Gln (c.3437G>A) is classified Conflicting classifications of pathogenicity in MYO7A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-06-13). AlphaMissense: ambiguous (0.5343); Ultra-rare (popmax 0.0205%, eas); Associated with MYO7A-related disorder.

What condition is associated with MYO7A p.Arg1146Gln (c.3437G>A)?

MYO7A p.Arg1146Gln (c.3437G>A) is associated with MYO7A-related disorder, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 2 (ClinVar).

How common is MYO7A p.Arg1146Gln (c.3437G>A) in the general population?

MYO7A p.Arg1146Gln (c.3437G>A) is ultra-rare (popmax 0.0205%, eas) (gnomAD).

What do computational predictors say about MYO7A p.Arg1146Gln (c.3437G>A)?

AlphaMissense predicts ambiguous (score 0.5343) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1146Gln

c.3437G>A · rs782140421 · VCV557475

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5343 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0205%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

MYO7A-related disorder

Computational evidence

Protein change
AlphaMissense	0.5343	ambiguous
REVEL	0.656	pathogenic-leaning
SaProt	LLR -6.12	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	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 0.0205% East Asian · 9/43,820 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00796%

Overall 0.00151% 24/1,588,260 alleles · ultra-rare exomes 21/1,436,052 · genomes 3/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0205%	4,869
Middle Eastern	0.0165%	6,064
Remaining individualsnot grpmax-eligible	0.00325%	30,754
Admixed American	0.00178%	56,216
European (non-Finnish)	0.000943%	106,088

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.Arg1146Gln
Coding: c.3437G>A
MANE Select: NM_000260
dbSNP: rs782140421
Type: single nucleotide variant
Location: chr11:77184649 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1146: the myth4 1 domain

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

Disease context

MYO7A-related disorder

Also linked: Usher syndrome type 1 autosomal recessive nonsyndromic hearing loss 2 Usher syndrome type 1B

Similar variants

MYO7A p.Arg1146Trp Uncertain significance ★★ ⚠ same residue
MYO7A p.Arg1146= 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-arg1146gln (accessed [today's date]).

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