Is AARS2 p.Ser40Leu (c.119C>T) pathogenic?

AARS2 p.Ser40Leu (c.119C>T) is classified Uncertain significance in AARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely benign (0.1063); Very rare (popmax 0.00017%, nfe).

How common is AARS2 p.Ser40Leu (c.119C>T) in the general population?

AARS2 p.Ser40Leu (c.119C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about AARS2 p.Ser40Leu (c.119C>T)?

AlphaMissense predicts likely benign (score 0.1063) — an in-silico prediction, not a clinical call.

AARS2 p.Ser40Leu

c.119C>T · rs778971317 · VCV1363840

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1063	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP -0.38, phastCons 0.92
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,178,550 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,456,430 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: AARS2
Protein: p.Ser40Leu
Coding: c.119C>T
MANE Select: NM_020745
dbSNP: rs778971317
Type: single nucleotide variant
Location: chr6:44313205 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.05 · 3 PDB

Full AARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AARS2 p.Ser40Trp Uncertain significance ★ ⚠ same residue
AARS2 p.Ser40= Likely benign ★ same residue
AARS2 c.2146-2A>G Pathogenic/Likely pathogenic ★★ same type
AARS2 c.2255+1G>A Pathogenic ★★ same type
AARS2 c.2598+1G>T Pathogenic/Likely pathogenic ★★ same type
AARS2 p.Arg199Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
AARS2 p.Arg521Ter Pathogenic ★★ same type
AARS2 p.Arg580Trp 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/aars2-p-ser40leu (accessed [today's date]).

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