Is USH2A p.Arg464His (c.1391G>A) pathogenic?

USH2A p.Arg464His (c.1391G>A) is classified Pathogenic/Likely pathogenic in USH2A (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.3048); Ultra-rare (popmax 0.0165%, mid); Associated with Usher syndrome type 2A.

What condition is associated with USH2A p.Arg464His (c.1391G>A)?

USH2A p.Arg464His (c.1391G>A) is associated with Usher syndrome type 2A, retinitis pigmentosa 39, inherited retinal dystrophy (ClinVar).

How common is USH2A p.Arg464His (c.1391G>A) in the general population?

USH2A p.Arg464His (c.1391G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about USH2A p.Arg464His (c.1391G>A)?

AlphaMissense predicts likely benign (score 0.3048) — an in-silico prediction, not a clinical call.

USH2A p.Arg464His

c.1391G>A · rs771000800 · VCV636117

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.3048 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Usher syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.3048	likely benign ⚠ discordant with ClinVar
REVEL	0.405	indeterminate
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 1.6, phastCons 0.97
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	23.3	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 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00155% 25/1,613,234 alleles · ultra-rare exomes 21/1,461,382 · genomes 4/151,852 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,076
East Asian	0.00893%	11,198
Admixed American	0.00501%	19,971
African / African-American	0.00401%	24,924
European (non-Finnish)	0.00119%	84,264

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.Arg464His
Coding: c.1391G>A
MANE Select: NM_206933
dbSNP: rs771000800
Type: single nucleotide variant
Location: chr1:216323633 (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 type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 39 inherited retinal dystrophy retinitis pigmentosa

Similar variants

USH2A p.Arg464Cys 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-arg464his (accessed [today's date]).

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