Is USH2A p.Ser1354= (c.4062A>G) pathogenic?

USH2A p.Ser1354= (c.4062A>G) is classified Likely benign in USH2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-12). Ultra-rare (popmax 0.0736%, eas); Associated with inherited retinal dystrophy.

What condition is associated with USH2A p.Ser1354= (c.4062A>G)?

USH2A p.Ser1354= (c.4062A>G) is associated with inherited retinal dystrophy (ClinVar).

How common is USH2A p.Ser1354= (c.4062A>G) in the general population?

USH2A p.Ser1354= (c.4062A>G) is ultra-rare (popmax 0.0736%, eas) (gnomAD).

USH2A p.Ser1354=

c.4062A>G · rs1173545767 · VCV1650910

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0736%, eas)

Conditions

inherited retinal dystrophy

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 -1.4	GERP -0.24
Overall
CADD	6.237	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0736% East Asian · 33/44,832 alleles

Filtering AF 0.0538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0471%

Overall 0.00204% 33/1,614,028 alleles · ultra-rare exomes 31/1,461,706 · genomes 2/152,322 · joint denominator

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.Ser1354=
Coding: c.4062A>G
MANE Select: NM_206933
dbSNP: rs1173545767
Type: single nucleotide variant
Location: chr1:216198334 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1354: the fibronectin type-iii 3 domain

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

Similar variants

USH2A p.Ser1354Ter Pathogenic ★ same residue
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-ser1354 (accessed [today's date]).

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