Is USH2A p.Pro4532fs (c.13595_13596del) pathogenic?

USH2A p.Pro4532fs (c.1359513596del) is classified Pathogenic/Likely pathogenic in USH2A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-04-14). Very rare (popmax 0.00401%, afr); Associated with USH2A-related disorder.

What condition is associated with USH2A p.Pro4532fs (c.13595_13596del)?

USH2A p.Pro4532fs (c.13595_13596del) is associated with USH2A-related disorder, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Pro4532fs (c.13595_13596del) in the general population?

USH2A p.Pro4532fs (c.13595_13596del) is very rare (popmax 0.00401%, afr) (gnomAD).

USH2A p.Pro4532fs

c.13595_13596del · rs1485393201 · VCV865801

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

USH2A-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 63 of 72
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.2	GERP 1.5, phastCons 0.98
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,852 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,742 alleles · very rare exomes 0/1,461,788 · genomes 3/151,954 · joint denominator

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.Pro4532fs
Coding: c.13595_13596del
MANE Select: NM_206933
dbSNP: rs1485393201
Type: Deletion
Location: chr1:215674315 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4532: the 'disordered' region

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

Disease context

Also linked: Usher syndrome type 2A retinitis pigmentosa 39

Similar variants

USH2A c.11389+1del Pathogenic/Likely pathogenic ★★ same condition
USH2A c.11549del Pathogenic/Likely pathogenic ★★ same condition
USH2A c.4251+1del Pathogenic/Likely pathogenic ★★ same condition
USH2A c.4758+1del Pathogenic/Likely pathogenic ★★ same condition
USH2A c.486-4_486-2del Likely pathogenic ★★ same condition
USH2A c.7594+2del Likely pathogenic ★★ same condition
USH2A c.9055+1del Pathogenic/Likely pathogenic ★★ same condition
USH2A p.Ala1312fs Pathogenic/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-pro4532fs (accessed [today's date]).

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