Is RARS2 p.Phe447fs (c.1340_1365del) pathogenic?

RARS2 p.Phe447fs (c.13401365del) is classified Pathogenic/Likely pathogenic in RARS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-24). Very rare (popmax 0.000424%, nfe); Associated with pontocerebellar hypoplasia type 6.

What condition is associated with RARS2 p.Phe447fs (c.1340_1365del)?

RARS2 p.Phe447fs (c.1340_1365del) is associated with pontocerebellar hypoplasia type 6 (ClinVar).

How common is RARS2 p.Phe447fs (c.1340_1365del) in the general population?

RARS2 p.Phe447fs (c.1340_1365del) is very rare (popmax 0.000424%, nfe) (gnomAD).

RARS2 p.Phe447fs

c.1340_1365del · rs1064795060 · VCV421326

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 0.000424%, nfe)

Conditions

pontocerebellar hypoplasia type 6

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 16 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.6	GERP 0.88, phastCons 1
Overall
CADD	36.0	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 0.000424% European (non-Finnish) · 5/1,179,970 alleles

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

Overall 0.000372% 6/1,613,898 alleles · very rare exomes 4/1,461,842 · genomes 2/152,056 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)grpmax	0.000424%	235,994

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe447fs
Coding: c.1340_1365del
MANE Select: NM_020320
dbSNP: rs1064795060
Type: Deletion
Location: chr6:87518680 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.18
Residue 447: 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 type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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.Arg519fs Pathogenic/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-phe447fs (accessed [today's date]).

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