Is USH2A p.Pro4521= (c.13563T>C) pathogenic?

USH2A p.Pro4521= (c.13563T>C) is classified Likely benign in USH2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Ultra-rare (popmax 0.08%, afr); Associated with Usher syndrome type 2A.

What condition is associated with USH2A p.Pro4521= (c.13563T>C)?

USH2A p.Pro4521= (c.13563T>C) is associated with Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Pro4521= (c.13563T>C) in the general population?

USH2A p.Pro4521= (c.13563T>C) is ultra-rare (popmax 0.08%, afr) (gnomAD).

USH2A p.Pro4521=

c.13563T>C · rs139701970 · VCV742389

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.08%, afr)

Conditions

Usher syndrome type 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.9	GERP -3
Overall
CADD	0.036	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.08% African / African-American · 60/74,984 alleles

Filtering AF 0.0637% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.00508% 82/1,613,822 alleles · ultra-rare exomes 48/1,461,688 · genomes 34/152,134 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.08%	1,250
Middle Eastern	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0192%	5,207
Admixed American	0.00333%	30,010
South Asian	0.0011%	91,070
European (non-Finnish)	0.000424%	235,967

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.Pro4521=
Coding: c.13563T>C
MANE Select: NM_206933
dbSNP: rs139701970
Type: single nucleotide variant
Location: chr1:215674348 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4521: the fibronectin type-iii 30 domain; the 'disordered' region

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

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-pro4521 (accessed [today's date]).

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