Is USH2A p.Ser290Ala (c.868T>G) pathogenic?

USH2A p.Ser290Ala (c.868T>G) is classified Uncertain significance in USH2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-11). AlphaMissense: likely benign (0.0969); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with USH2A p.Ser290Ala (c.868T>G)?

USH2A p.Ser290Ala (c.868T>G) is associated with Inborn genetic diseases (ClinVar).

How common is USH2A p.Ser290Ala (c.868T>G) in the general population?

USH2A p.Ser290Ala (c.868T>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about USH2A p.Ser290Ala (c.868T>G)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

USH2A p.Ser290Ala

c.868T>G · rs746122630 · VCV2281530

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
REVEL	0.183	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.19, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	16.84	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,574 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,260 alleles · very rare exomes 3/1,461,036 · genomes 0/152,224 · 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.Ser290Ala
Coding: c.868T>G
MANE Select: NM_206933
dbSNP: rs746122630
Type: single nucleotide variant
Location: chr1:216325580 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 290: the laminin n-terminal domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

USH2A p.Ser290Pro Uncertain significance ★ same residue
USH2A p.Ser290= Likely benign ★ same residue
USH2A p.Ser290Phe Uncertain significance same residue
USH2A p.Gln4900Ter Pathogenic/Likely pathogenic ★★ same condition
USH2A p.Ala1617Val Uncertain significance ★★ same condition
USH2A p.Ala1877Glu Uncertain significance ★★ same condition
USH2A p.Ala1952Val Uncertain significance ★★ ⚠ same condition
USH2A p.Ala2111Glu Uncertain significance ★★ ⚠ 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-ser290ala (accessed [today's date]).

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