Is MYO7A p.Arg1463Cys (c.4387C>T) pathogenic?

MYO7A p.Arg1463Cys (c.4387C>T) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-08). AlphaMissense: ambiguous (0.3439); Ultra-rare (popmax 0.0168%, nfe); Associated with Usher syndrome type 1B.

What condition is associated with MYO7A p.Arg1463Cys (c.4387C>T)?

MYO7A p.Arg1463Cys (c.4387C>T) is associated with Usher syndrome type 1B (ClinVar).

How common is MYO7A p.Arg1463Cys (c.4387C>T) in the general population?

MYO7A p.Arg1463Cys (c.4387C>T) is ultra-rare (popmax 0.0168%, nfe) (gnomAD).

What do computational predictors say about MYO7A p.Arg1463Cys (c.4387C>T)?

AlphaMissense predicts ambiguous (score 0.3439) — an in-silico prediction, not a clinical call.

MYO7A p.Arg1463Cys

c.4387C>T · rs202111392 · VCV851288

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3439 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Usher syndrome type 1B

Computational evidence

Protein change
AlphaMissense	0.3439	ambiguous
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -11.82	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	28.3	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 0.0168% European (non-Finnish) · 198/1,177,258 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0142%

Overall 0.0132% 212/1,608,204 alleles · ultra-rare exomes 200/1,455,860 · genomes 12/152,344 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0168%	5,946
Middle Eastern	0.0165%	6,052
Remaining individualsnot grpmax-eligible	0.00802%	12,463
African / African-American	0.004%	24,985
Admixed American	0.00337%	29,666
East Asian	0.00223%	44,752
South Asian	0.00223%	44,758

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.Arg1463Cys
Coding: c.4387C>T
MANE Select: NM_000260
dbSNP: rs202111392
Type: single nucleotide variant
Location: chr11:77197544 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1463: the ferm 1 domain

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

Disease context

Usher syndrome type 1B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MYO7A p.Arg1463His 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
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-arg1463cys (accessed [today's date]).

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