Is USH2A p.Phe1859= (c.5577C>T) pathogenic?

USH2A p.Phe1859= (c.5577C>T) is classified Likely benign in USH2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0336%, eas); Associated with inherited retinal dystrophy.

What condition is associated with USH2A p.Phe1859= (c.5577C>T)?

USH2A p.Phe1859= (c.5577C>T) is associated with inherited retinal dystrophy, Usher syndrome type 2A (ClinVar).

How common is USH2A p.Phe1859= (c.5577C>T) in the general population?

USH2A p.Phe1859= (c.5577C>T) is ultra-rare (popmax 0.0336%, eas) (gnomAD).

USH2A p.Phe1859=

c.5577C>T · rs764839361 · VCV729600

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0336%, eas)

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.55 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.9	GERP 0.23, phastCons 0.92
Overall
CADD	11.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0336% East Asian · 15/44,656 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00707% 114/1,611,888 alleles · ultra-rare exomes 103/1,461,390 · genomes 11/150,498 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0336%	2,977
Finnishnot grpmax-eligible	0.011%	9,122
Remaining individualsnot grpmax-eligible	0.00801%	12,486
European (non-Finnish)	0.00687%	14,564
African / African-American	0.00673%	14,855
Admixed American	0.00168%	59,592

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.Phe1859=
Coding: c.5577C>T
MANE Select: NM_206933
dbSNP: rs764839361
Type: single nucleotide variant
Location: chr1:216073296 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1859: the laminin g-like 2 domain; a UniProt-annotated variant site (in rp39)

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

Also linked: Usher syndrome type 2A

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-phe1859 (accessed [today's date]).

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