Is USH2A p.Glu1663Ter (c.4987G>T) pathogenic?

USH2A p.Glu1663Ter (c.4987G>T) is classified Likely pathogenic in USH2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). Absent from gnomAD v4.1; Associated with retinitis pigmentosa 39.

What condition is associated with USH2A p.Glu1663Ter (c.4987G>T)?

USH2A p.Glu1663Ter (c.4987G>T) is associated with retinitis pigmentosa 39, Usher syndrome type 2A (ClinVar).

How common is USH2A p.Glu1663Ter (c.4987G>T) in the general population?

USH2A p.Glu1663Ter (c.4987G>T) is absent from gnomAD v4.1 (gnomAD).

How is Retinitis pigmentosa inherited?

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

USH2A p.Glu1663Ter

c.4987G>T · VCV3579179

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

retinitis pigmentosa 39

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 24 of 72
Splicing
SpliceAI	Δ0.32	donor gain · deltas
Pangolin	Δ0.60	gain · loss 0.59 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.2	GERP 1.8, phastCons 1
Overall
CADD	45.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: USH2A
Protein: p.Glu1663Ter
Coding: c.4987G>T
MANE Select: NM_206933
Type: single nucleotide variant
Location: chr1:216086719 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1663: the laminin g-like 1 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 p.Glu1663= 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
USH2A p.Arg4192Cys Likely pathogenic ★★★ ⚠ same condition
USH2A p.Asn346His 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-glu1663ter (accessed [today's date]).

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