Is USH2A p.His752= (c.2256T>C) pathogenic?

USH2A p.His752= (c.2256T>C) is classified Benign/Likely benign in USH2A (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-01-28). Rare (popmax 0.185%, amr); Associated with Usher syndrome type 2A.

What condition is associated with USH2A p.His752= (c.2256T>C)?

USH2A p.His752= (c.2256T>C) is associated with Usher syndrome type 2A, retinitis pigmentosa 39, retinitis pigmentosa (ClinVar).

How common is USH2A p.His752= (c.2256T>C) in the general population?

USH2A p.His752= (c.2256T>C) is rare (popmax 0.185%, amr) (gnomAD).

USH2A p.His752=

c.2256T>C · rs111033281 · VCV48486

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

rare (popmax 0.185%, amr)

Conditions

Usher syndrome type 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.4	GERP -3.8
Overall
CADD	0.408	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.185% Admixed American · 111/60,006 alleles

Filtering AF 0.157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.107% 1,727/1,614,044 alleles · rare exomes 1,576/1,461,764 · genomes 151/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.185%	541
European (non-Finnish)	0.128%	778
Remaining individualsnot grpmax-eligible	0.12%	833
African / African-American	0.0306%	3,263
Finnishnot grpmax-eligible	0.00312%	32,014

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.His752=
Coding: c.2256T>C
MANE Select: NM_206933
dbSNP: rs111033281
Type: single nucleotide variant
Location: chr1:216247138 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 752: the laminin egf-like 5 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 retinitis pigmentosa

Similar variants

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
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-his752 (accessed [today's date]).

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