Is USH2A p.Thr2129= (c.6387A>G) pathogenic?

USH2A p.Thr2129= (c.6387A>G) is classified Likely benign in USH2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-25). Rare (popmax 0.165%, mid); Associated with Usher syndrome type 2A.

What condition is associated with USH2A p.Thr2129= (c.6387A>G)?

USH2A p.Thr2129= (c.6387A>G) is associated with Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Thr2129= (c.6387A>G) in the general population?

USH2A p.Thr2129= (c.6387A>G) is rare (popmax 0.165%, mid) (gnomAD).

USH2A p.Thr2129=

c.6387A>G · rs150282853 · VCV739654

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

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 -1.2	GERP -2.9, phastCons 0.002
Overall
CADD	4.501	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.165% Middle Eastern · 10/6,060 alleles

Filtering AF 0.0895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.0206% 333/1,613,736 alleles · rare exomes 303/1,461,422 · genomes 30/152,314 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	606
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,972
Remaining individualsnot grpmax-eligible	0.0384%	2,603
European (non-Finnish)	0.0231%	4,337
Admixed American	0.01%	9,996
South Asian	0.00549%	18,216
African / African-American	0.00133%	75,032

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.Thr2129=
Coding: c.6387A>G
MANE Select: NM_206933
dbSNP: rs150282853
Type: single nucleotide variant
Location: chr1:216000501 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2129: the fibronectin type-iii 7 domain

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 p.Thr2129Ala Uncertain significance ★ ⚠ 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-thr2129 (accessed [today's date]).

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