Is USH2A p.His667= (c.2001C>T) pathogenic?

USH2A p.His667= (c.2001C>T) is classified Conflicting classifications of pathogenicity in USH2A (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-01). Rare (popmax 0.22%, afr); Associated with retinitis pigmentosa.

What condition is associated with USH2A p.His667= (c.2001C>T)?

USH2A p.His667= (c.2001C>T) is associated with retinitis pigmentosa, Usher syndrome type 2A (ClinVar).

How common is USH2A p.His667= (c.2001C>T) in the general population?

USH2A p.His667= (c.2001C>T) is rare (popmax 0.22%, afr) (gnomAD).

How is Retinitis pigmentosa inherited?

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

USH2A p.His667=

c.2001C>T · rs142870255 · VCV178582

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.22%, afr)

Conditions

retinitis pigmentosa

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 0.038	GERP -3.1
Overall
CADD	4.379	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.22% African / African-American · 165/75,018 alleles

Filtering AF 0.193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.182%

Overall 0.0176% 284/1,613,972 alleles · rare exomes 197/1,461,752 · genomes 87/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.22%	455
Middle Eastern	0.215%	466
Remaining individualsnot grpmax-eligible	0.0512%	1,953
Admixed American	0.04%	2,500
South Asian	0.00549%	18,216
European (non-Finnish)	0.00373%	26,818
Finnishnot grpmax-eligible	0.00156%	64,008

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.His667=
Coding: c.2001C>T
MANE Select: NM_206933
dbSNP: rs142870255
Type: single nucleotide variant
Location: chr1:216251069 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 667: the laminin egf-like 3 domain

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

Disease context

retinitis pigmentosa — 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.His667Gln 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-his667 (accessed [today's date]).

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