Is HARS1 p.Arg63= (c.189A>G) pathogenic?

HARS1 p.Arg63= (c.189A>G) is classified Likely benign in HARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). Very rare (popmax 0.000424%, nfe); Associated with Usher syndrome type 3B.

What condition is associated with HARS1 p.Arg63= (c.189A>G)?

HARS1 p.Arg63= (c.189A>G) is associated with Usher syndrome type 3B (ClinVar).

How common is HARS1 p.Arg63= (c.189A>G) in the general population?

HARS1 p.Arg63= (c.189A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

HARS1 p.Arg63=

c.189A>G · rs1490820133 · VCV2714668

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

Usher syndrome type 3B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.91	GERP 2, phastCons 1
Overall
CADD	13.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,802 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,680 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: HARS1
Protein: p.Arg63=
Coding: c.189A>G
MANE Select: NM_002109
dbSNP: rs1490820133
Type: single nucleotide variant
Location: chr5:140683211 (GRCh38)
Gene constraint: LOEUF 0.957 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.06 · 10 PDB

Full HARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Usher syndrome type 3B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HARS1 p.Arg63Lys Uncertain significance ★ ⚠ same residue
HARS1 c.1195-1G>A Uncertain significance ★★ same condition
HARS1 c.1311+4T>C Uncertain significance ★★ same condition
HARS1 c.1312-1G>A Uncertain significance ★★ same condition
HARS1 c.631-3C>A Uncertain significance ★★ same condition
HARS1 c.90+4A>C Uncertain significance ★★ same condition
HARS1 c.952-3C>A Uncertain significance ★★ same condition
HARS1 p.Ala2Thr 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/hars1-p-arg63 (accessed [today's date]).

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