Is USH2A p.Ser180Pro (c.538T>C) pathogenic?

USH2A p.Ser180Pro (c.538T>C) is classified Pathogenic in USH2A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-22). AlphaMissense: likely pathogenic (0.9248); Very rare (popmax 0.0067%, eas); Associated with Usher syndrome.

What condition is associated with USH2A p.Ser180Pro (c.538T>C)?

USH2A p.Ser180Pro (c.538T>C) is associated with Usher syndrome, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Ser180Pro (c.538T>C) in the general population?

USH2A p.Ser180Pro (c.538T>C) is very rare (popmax 0.0067%, eas) (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.Ser180Pro (c.538T>C)?

AlphaMissense predicts likely pathogenic (score 0.9248) — an in-silico prediction, not a clinical call.

USH2A p.Ser180Pro

c.538T>C · rs1171672823 · VCV554033

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9248 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0067%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Usher syndrome

Computational evidence

Protein change
AlphaMissense	0.9248	likely pathogenic ✓ concordant with ClinVar · top 1% in USH2A
REVEL	0.759	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 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	24.0	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 0.0067% East Asian · 3/44,806 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000205% 3/1,461,074 alleles · very rare

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.Ser180Pro
Coding: c.538T>C
MANE Select: NM_206933
dbSNP: rs1171672823
Type: single nucleotide variant
Location: chr1:216418627 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 180: a UniProt-annotated variant site (in ush2a)

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.Ser180= Likely benign ★ 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-ser180pro (accessed [today's date]).

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