Is USH2A p.Cys620Phe (c.1859G>T) pathogenic?

USH2A p.Cys620Phe (c.1859G>T) is classified Pathogenic in USH2A (ClinVar, Expert panel, 12 submitters; last evaluated 2023-10-24). AlphaMissense: likely pathogenic (0.9244); Very rare (popmax 0.00729%, nfe); Associated with Usher syndrome.

What condition is associated with USH2A p.Cys620Phe (c.1859G>T)?

USH2A p.Cys620Phe (c.1859G>T) is associated with Usher syndrome, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Cys620Phe (c.1859G>T) in the general population?

USH2A p.Cys620Phe (c.1859G>T) is very rare (popmax 0.00729%, nfe) (gnomAD).

How is Usher syndrome inherited?

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

What do computational predictors say about USH2A p.Cys620Phe (c.1859G>T)?

AlphaMissense predicts likely pathogenic (score 0.9244) — an in-silico prediction, not a clinical call.

USH2A p.Cys620Phe

c.1859G>T · rs758571672 · VCV549981

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.9244 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00729%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Usher syndrome

ClinGen expert panel — Hearing Loss VCEP

Pathogenic for Usher syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting PM3_VeryStrong PP1 PP3 PP4

Curation rationale (ClinGen, verbatim)

The c.1859G>T in USH2A is a missense variant predicted to cause a substitution of cysteine to phenylalanine at amino acid 620 (p.Cys620Phe) . The highest population minor allele frequency in gnomAD v2.1.1 is 0.004% (5/129062) in the European(non-Finnish) sub-population which is below the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.974 (PP3). This variant has been detected in at least four probands with other pathogenic or suspected-pathogenic variants confirmed in trans (4.0 PM3_Very Strong points; PMID: 22135276, 33089500, 36011334). The probands harbored these variants in USH2A: p.Trp1607*, p.Glu767Serfs*21, p.Cys759Phe, p.Gly3195*. At least one patient displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A and Usher syndrome (PP4; PMID: 22135276). The variant has been reported to segregate with AR Usher syndrome in one affected family member from one family (PP1; PMID: 36011334). In summary, this variant meets the criteria to be classified as pathogenic for AR Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Very Strong, PP4, PP1. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9244	likely pathogenic ✓ concordant with ClinVar · top 1% in USH2A
REVEL	0.974	strongly pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00729% European (non-Finnish) · 86/1,179,830 alleles

Filtering AF 0.00604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00557%

Overall 0.00545% 88/1,613,804 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00729%	13,719
Remaining individualsnot grpmax-eligible	0.0032%	31,238

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.Cys620Phe
Coding: c.1859G>T
MANE Select: NM_206933
dbSNP: rs758571672
Type: single nucleotide variant
Location: chr1:216289392 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 620: a disulfide bond; the laminin egf-like 2 domain

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

Disease context

Usher syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 2A retinitis pigmentosa 39

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

USH2A p.Cys620Ter Pathogenic 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-cys620phe (accessed [today's date]).

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