Is USH2A p.Pro2000Ser (c.5998C>T) pathogenic?

USH2A p.Pro2000Ser (c.5998C>T) is classified Uncertain significance in USH2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-31). AlphaMissense: likely benign (0.0686); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with USH2A p.Pro2000Ser (c.5998C>T)?

USH2A p.Pro2000Ser (c.5998C>T) is associated with Inborn genetic diseases (ClinVar).

How common is USH2A p.Pro2000Ser (c.5998C>T) in the general population?

USH2A p.Pro2000Ser (c.5998C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USH2A p.Pro2000Ser (c.5998C>T)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

USH2A p.Pro2000Ser

c.5998C>T · rs2102546066 · VCV2030568

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -2.9, phastCons 0.94
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	3.757	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

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.Pro2000Ser
Coding: c.5998C>T
MANE Select: NM_206933
dbSNP: rs2102546066
Type: single nucleotide variant
Location: chr1:216070152 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2000: the fibronectin type-iii 6 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USH2A p.Gln4900Ter Pathogenic/Likely pathogenic ★★ same condition
USH2A p.Ala1617Val Uncertain significance ★★ same condition
USH2A p.Ala1877Glu Uncertain significance ★★ same condition
USH2A p.Ala1952Val Uncertain significance ★★ ⚠ same condition
USH2A p.Ala2111Glu Uncertain significance ★★ ⚠ same condition
USH2A p.Ala2234Val Uncertain significance ★★ ⚠ same condition
USH2A p.Ala2246Asp Uncertain significance ★★ ⚠ same condition
USH2A p.Ala2459Gly Uncertain significance ★★ ⚠ 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-pro2000ser (accessed [today's date]).

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