Is RARS2 p.Ser239Pro (c.715T>C) pathogenic?

RARS2 p.Ser239Pro (c.715T>C) is classified Uncertain significance in RARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-18). AlphaMissense: likely benign (0.2808); Very rare (popmax 8.47e-05%, nfe).

How common is RARS2 p.Ser239Pro (c.715T>C) in the general population?

RARS2 p.Ser239Pro (c.715T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about RARS2 p.Ser239Pro (c.715T>C)?

AlphaMissense predicts likely benign (score 0.2808) — an in-silico prediction, not a clinical call.

RARS2 p.Ser239Pro

c.715T>C · VCV3691355

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2808	likely benign
REVEL	0.343	indeterminate
SaProt	LLR -12.30	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 76 kb · p 0.44 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.2e-05% 1/1,614,060 alleles · very rare exomes 0/1,461,866 · genomes 1/152,194 · 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: RARS2
Protein: p.Ser239Pro
Coding: c.715T>C
MANE Select: NM_020320
Type: single nucleotide variant
Location: chr6:87530840 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.18

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

Similar variants

RARS2 p.Ser239Ter Pathogenic/Likely pathogenic ★★ same residue
RARS2 p.Ser239Leu Uncertain significance ★ ⚠ same residue
RARS2 p.Ser239= Likely benign ★ same residue
RARS2 c.1035+2T>G Likely pathogenic ★★ same type
RARS2 c.110+5A>G Pathogenic/Likely pathogenic ★★ same type
RARS2 c.111-2A>G Likely pathogenic ★★ same type
RARS2 c.1113-2A>G Likely pathogenic ★★ same type
RARS2 c.1237+1G>A Pathogenic/Likely pathogenic ★★ same type

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-ser239pro (accessed [today's date]).

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