Is USH2A p.Arg4468= (c.13404A>G) pathogenic?

USH2A p.Arg4468= (c.13404A>G) is classified Benign/Likely benign in USH2A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). Rare (popmax 0.817%, afr); Associated with retinitis pigmentosa 39.

What condition is associated with USH2A p.Arg4468= (c.13404A>G)?

USH2A p.Arg4468= (c.13404A>G) is associated with retinitis pigmentosa 39, Usher syndrome type 2A (ClinVar).

How common is USH2A p.Arg4468= (c.13404A>G) in the general population?

USH2A p.Arg4468= (c.13404A>G) is rare (popmax 0.817%, afr) (gnomAD).

How is Retinitis pigmentosa inherited?

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

USH2A p.Arg4468=

c.13404A>G · rs146994147 · VCV48418

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.817%, afr)

Conditions

retinitis pigmentosa 39

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.012	GERP 0.5
Overall
CADD	6.827	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.817% African / African-American · 613/75,066 alleles

Filtering AF 0.763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.742%

Overall 0.0419% 677/1,614,192 alleles · rare exomes 342/1,461,870 · genomes 335/152,322 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.817%	122
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.04%	2,500
Admixed American	0.0383%	2,610
European (non-Finnish)	0.00102%	98,335

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.Arg4468=
Coding: c.13404A>G
MANE Select: NM_206933
dbSNP: rs146994147
Type: single nucleotide variant
Location: chr1:215674507 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4468: the fibronectin type-iii 30 domain

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

Disease context

retinitis pigmentosa 39 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 2A

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

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
USH2A p.Arg4192Cys Likely pathogenic ★★★ ⚠ same condition
USH2A p.Asn346His Pathogenic ★★★ same condition
USH2A p.Asn4292Asp 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/ush2a-p-arg4468 (accessed [today's date]).

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