Is RARS2 p.Arg519fs (c.1554del) pathogenic?

RARS2 p.Arg519fs (c.1554del) is classified Pathogenic/Likely pathogenic in RARS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-11). Very rare (popmax 0.00333%, amr); Associated with pontocerebellar hypoplasia.

What condition is associated with RARS2 p.Arg519fs (c.1554del)?

RARS2 p.Arg519fs (c.1554del) is associated with pontocerebellar hypoplasia, pontocerebellar hypoplasia type 6 (ClinVar).

How common is RARS2 p.Arg519fs (c.1554del) in the general population?

RARS2 p.Arg519fs (c.1554del) is very rare (popmax 0.00333%, amr) (gnomAD).

RARS2 p.Arg519fs

c.1554del · rs754610170 · VCV1032075

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

pontocerebellar hypoplasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 0.45, phastCons 1
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,002 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00248% 40/1,613,778 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,001
European (non-Finnish)	0.00314%	31,889
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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: RARS2
Protein: p.Arg519fs
Coding: c.1554del
MANE Select: NM_020320
dbSNP: rs754610170
Type: Deletion
Location: chr6:87516838 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.18
Residue 519: a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy and dementia; uncertain significance)

Full RARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pontocerebellar hypoplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pontocerebellar hypoplasia type 6

Similar variants

RARS2 p.Arg519Gly Uncertain significance ★★ ⚠ same residue
RARS2 c.1650+1del Pathogenic/Likely pathogenic ★★ same condition
RARS2 c.395+1_395+9del Likely pathogenic ★★ same condition
RARS2 c.879-2del Likely pathogenic ★★ same condition
RARS2 p.Asn93fs Pathogenic/Likely pathogenic ★★ same condition
RARS2 p.Asp53_Asn54insTer Pathogenic/Likely pathogenic ★★ same condition
RARS2 p.Asp543fs Likely pathogenic ★★ same condition
RARS2 p.Gln277fs Pathogenic/Likely 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/rars2-p-arg519fs (accessed [today's date]).

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