Is USH2A p.Thr1997Ile (c.5990C>T) pathogenic?

USH2A p.Thr1997Ile (c.5990C>T) is classified Uncertain significance in USH2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-01). AlphaMissense: likely benign (0.0764); Very rare (popmax 0.00669%, eas); Associated with inherited retinal dystrophy.

What condition is associated with USH2A p.Thr1997Ile (c.5990C>T)?

USH2A p.Thr1997Ile (c.5990C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is USH2A p.Thr1997Ile (c.5990C>T) in the general population?

USH2A p.Thr1997Ile (c.5990C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about USH2A p.Thr1997Ile (c.5990C>T)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

USH2A p.Thr1997Ile

c.5990C>T · rs2031510445 · VCV1506988

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.05	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 0.27	GERP -0.65
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	5.463	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

Grpmax group 0.00669% East Asian · 3/44,864 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000205% 3/1,461,752 alleles · very rare

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.Thr1997Ile
Coding: c.5990C>T
MANE Select: NM_206933
dbSNP: rs2031510445
Type: single nucleotide variant
Location: chr1:216070160 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1997: the fibronectin type-iii 6 domain

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USH2A p.Thr1997= Likely benign ★ same residue
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-thr1997ile (accessed [today's date]).

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