Is USH2A p.Pro4378Ser (c.13132C>T) pathogenic?

USH2A p.Pro4378Ser (c.13132C>T) is classified Uncertain significance in USH2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). AlphaMissense: likely benign (0.1121); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with USH2A p.Pro4378Ser (c.13132C>T)?

USH2A p.Pro4378Ser (c.13132C>T) is associated with Inborn genetic diseases (ClinVar).

How common is USH2A p.Pro4378Ser (c.13132C>T) in the general population?

USH2A p.Pro4378Ser (c.13132C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about USH2A p.Pro4378Ser (c.13132C>T)?

AlphaMissense predicts likely benign (score 0.1121) — an in-silico prediction, not a clinical call.

USH2A p.Pro4378Ser

c.13132C>T · VCV4634257

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1121 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1121	likely benign
REVEL	0.332	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	18.07	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: USH2A
Protein: p.Pro4378Ser
Coding: c.13132C>T
MANE Select: NM_206933
Type: single nucleotide variant
Location: chr1:215674779 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4378: the fibronectin type-iii 29 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.Pro4378= Likely benign ★★ same residue
USH2A p.Pro4378Gln Uncertain significance ★ same residue
USH2A p.Pro4378Leu Conflicting classifications of pathogenicity ★ same residue
USH2A p.Gln4900Ter Pathogenic/Likely pathogenic ★★ same condition
USH2A p.Pro4378fs Pathogenic/Likely pathogenic ★★ same residue
USH2A p.Ala1617Val Uncertain significance ★★ same condition
USH2A p.Ala1877Glu Uncertain significance ★★ same condition
USH2A p.Ala1952Val 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-pro4378ser (accessed [today's date]).

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