Is USH2A p.Pro1104Arg (c.3311C>G) pathogenic?

USH2A p.Pro1104Arg (c.3311C>G) is classified Uncertain significance in USH2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-02). AlphaMissense: ambiguous (0.3565); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with USH2A p.Pro1104Arg (c.3311C>G)?

USH2A p.Pro1104Arg (c.3311C>G) is associated with Inborn genetic diseases (ClinVar).

How common is USH2A p.Pro1104Arg (c.3311C>G) in the general population?

USH2A p.Pro1104Arg (c.3311C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about USH2A p.Pro1104Arg (c.3311C>G)?

AlphaMissense predicts ambiguous (score 0.3565) — an in-silico prediction, not a clinical call.

USH2A p.Pro1104Arg

c.3311C>G · rs778168432 · VCV1471818

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3565 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3565	ambiguous
REVEL	0.546	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	24.1	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 0.000254% European (non-Finnish) · 3/1,179,884 alleles

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

Overall 0.000205% 3/1,461,662 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.Pro1104Arg
Coding: c.3311C>G
MANE Select: NM_206933
dbSNP: rs778168432
Type: single nucleotide variant
Location: chr1:216207278 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1104: the fibronectin type-iii 1 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.Pro1104Thr 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
USH2A p.Ala2234Val Uncertain significance ★★ ⚠ same condition
USH2A p.Ala2246Asp 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-pro1104arg (accessed [today's date]).

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