Is MYO7A p.Arg1408Gly (c.4222C>G) pathogenic?

MYO7A p.Arg1408Gly (c.4222C>G) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-06-22). AlphaMissense: likely pathogenic (0.9246); Very rare (popmax 0.00984%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MYO7A p.Arg1408Gly (c.4222C>G)?

MYO7A p.Arg1408Gly (c.4222C>G) is associated with Inborn genetic diseases, Usher syndrome type 1B (ClinVar).

How common is MYO7A p.Arg1408Gly (c.4222C>G) in the general population?

MYO7A p.Arg1408Gly (c.4222C>G) is very rare (popmax 0.00984%, nfe) (gnomAD).

What do computational predictors say about MYO7A p.Arg1408Gly (c.4222C>G)?

AlphaMissense predicts likely pathogenic (score 0.9246) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1408Gly

c.4222C>G · rs377391891 · VCV178487

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9246 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00984%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9246	likely pathogenic
REVEL	0.56	indeterminate
SaProt	LLR -9.70	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	25.4	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 0.00984% European (non-Finnish) · 116/1,179,190 alleles

Filtering AF 0.00835% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00777%

Overall 0.00763% 123/1,612,056 alleles · very rare exomes 115/1,459,862 · genomes 8/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00984%	10,165
Remaining individualsnot grpmax-eligible	0.00961%	10,401
African / African-American	0.00134%	74,906

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.Arg1408Gly
Coding: c.4222C>G
MANE Select: NM_000260
dbSNP: rs377391891
Type: single nucleotide variant
Location: chr11:77194423 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1408: the ferm 1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1B

Similar variants

MYO7A p.Arg1408Cys Uncertain significance ★★ ⚠ same residue
MYO7A p.Arg1408His 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-arg1408gly (accessed [today's date]).

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