Is MYO7A p.Arg1408Cys (c.4222C>T) pathogenic?

MYO7A p.Arg1408Cys (c.4222C>T) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-27). AlphaMissense: likely pathogenic (0.8647); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with MYO7A p.Arg1408Cys (c.4222C>T)?

MYO7A p.Arg1408Cys (c.4222C>T) is associated with Inborn genetic diseases, Usher syndrome type 1, Usher syndrome type 1B (ClinVar).

How common is MYO7A p.Arg1408Cys (c.4222C>T) in the general population?

MYO7A p.Arg1408Cys (c.4222C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about MYO7A p.Arg1408Cys (c.4222C>T)?

AlphaMissense predicts likely pathogenic (score 0.8647) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1408Cys

c.4222C>T · rs377391891 · VCV499163

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8647	likely pathogenic
REVEL	0.654	pathogenic-leaning
SaProt	LLR -11.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,906 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00174% 28/1,612,056 alleles · very rare exomes 26/1,459,862 · genomes 2/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,726
Admixed American	0.00502%	19,929
East Asian	0.00223%	44,828
Remaining individualsnot grpmax-eligible	0.0016%	62,408
European (non-Finnish)	0.00153%	65,511
South Asian	0.00111%	90,486

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.Arg1408Cys
Coding: c.4222C>T
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 1 Usher syndrome type 1B

Similar variants

MYO7A p.Arg1408Gly 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-arg1408cys (accessed [today's date]).

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