Is USH2A p.Arg464Cys (c.1390C>T) pathogenic?

USH2A p.Arg464Cys (c.1390C>T) is classified Pathogenic/Likely pathogenic in USH2A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.6096); Very rare (popmax 0.00223%, eas); Associated with Usher syndrome.

What condition is associated with USH2A p.Arg464Cys (c.1390C>T)?

USH2A p.Arg464Cys (c.1390C>T) is associated with Usher syndrome, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Arg464Cys (c.1390C>T) in the general population?

USH2A p.Arg464Cys (c.1390C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Usher syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about USH2A p.Arg464Cys (c.1390C>T)?

AlphaMissense predicts likely pathogenic (score 0.6096) — an in-silico prediction, not a clinical call.

USH2A p.Arg464Cys

c.1390C>T · rs1423536179 · VCV551303

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.6096 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Usher syndrome

Computational evidence

Protein change
AlphaMissense	0.6096	likely pathogenic ✓ concordant with ClinVar
REVEL	0.461	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,788 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,613,576 alleles · very rare exomes 6/1,461,390 · genomes 0/152,186 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,788
South Asian	0.0011%	91,070
European (non-Finnish)	0.000339%	294,930

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: USH2A
Protein: p.Arg464Cys
Coding: c.1390C>T
MANE Select: NM_206933
dbSNP: rs1423536179
Type: single nucleotide variant
Location: chr1:216323634 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 464: a UniProt-annotated variant site (in ush2a; uncertain significance); the laminin n-terminal domain

Full USH2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Usher syndrome type 2A retinitis pigmentosa 39 inherited retinal dystrophy

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

USH2A p.Arg464His Pathogenic/Likely pathogenic ★★ ⚠ same residue
USH2A p.Arg464Leu Uncertain significance ★ same residue
USH2A p.Arg464= Likely benign ★ same residue
USH2A c.12295-3T>A Pathogenic ★★★ same condition
USH2A c.8559-2A>G Pathogenic ★★★ same condition
USH2A c.8682-9A>G Pathogenic ★★★ same condition
USH2A p.Ala4740Asp Pathogenic ★★★ ⚠ same condition
USH2A p.Arg3905Cys 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/ush2a-p-arg464cys (accessed [today's date]).

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