Is USH2A p.Pro2149Gln (c.6446C>A) pathogenic?

USH2A p.Pro2149Gln (c.6446C>A) is classified Uncertain significance in USH2A (ClinVar, Expert panel, 4 submitters; last evaluated 2025-04-16). AlphaMissense: likely pathogenic (0.7404); Very rare (popmax 0.000593%, nfe); Associated with Usher syndrome.

What condition is associated with USH2A p.Pro2149Gln (c.6446C>A)?

USH2A p.Pro2149Gln (c.6446C>A) is associated with Usher syndrome, Usher syndrome type 2A, inherited retinal dystrophy (ClinVar).

How common is USH2A p.Pro2149Gln (c.6446C>A) in the general population?

USH2A p.Pro2149Gln (c.6446C>A) is very rare (popmax 0.000593%, nfe) (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.Pro2149Gln (c.6446C>A)?

AlphaMissense predicts likely pathogenic (score 0.7404) — an in-silico prediction, not a clinical call.

USH2A p.Pro2149Gln

c.6446C>A · rs869312182 · VCV224753

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7404 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

Usher syndrome

ClinGen expert panel — Hearing Loss VCEP

Uncertain Significance for Usher syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting PP4 PM3

Curation rationale (ClinGen, verbatim)

The NM_206933.4:c.6446C>A variant in the USH2A gene is a missense variant predicted to cause the substitution of proline by glutamine at amino acid 2149 (p.Pro2149Gln). The minor allele frequency of this variant in gnomAD v.4.1.0 was 0.00059% (7/1179718 alleles) in the European (non-Finnish) population meeting PM2_Supporting. The REVEL computational prediction analysis tool produced a score of 0.355, which doesn’t meet either of the thresholds necessary to apply PP3/BP4. It has been detected with another suspected pathogenic variant in two patients with Usher syndrome type 2, of which one patient displayed hearing loss with an onset in the first decade and retinitis pigmentosa with an onset at 22y.o, which is specific for Usher syndrome (PM3, PP4; PMIDs: 26872967, 29074561, 32176120, 31836858). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: PM3, PM2_Supporting, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 4/16/2025).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.7404	likely pathogenic · top 7% in USH2A
REVEL	0.355	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	22.4	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 0.000593% European (non-Finnish) · 7/1,179,718 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,662 alleles · very rare exomes 7/1,461,376 · genomes 0/152,286 · 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.Pro2149Gln
Coding: c.6446C>A
MANE Select: NM_206933
dbSNP: rs869312182
Type: single nucleotide variant
Location: chr1:216000442 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2149: the fibronectin type-iii 8 domain

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 inherited retinal dystrophy retinitis pigmentosa

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

USH2A p.Pro2149= 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-pro2149gln (accessed [today's date]).

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