Is AARS2 p.Arg101His (c.302G>A) pathogenic?

AARS2 p.Arg101His (c.302G>A) is classified Uncertain significance in AARS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-14). AlphaMissense: likely benign (0.1739); Very rare (popmax 0.00667%, afr); Associated with leukoencephalopathy, progressive, with ovarian failure.

What condition is associated with AARS2 p.Arg101His (c.302G>A)?

AARS2 p.Arg101His (c.302G>A) is associated with leukoencephalopathy, progressive, with ovarian failure (ClinVar).

How common is AARS2 p.Arg101His (c.302G>A) in the general population?

AARS2 p.Arg101His (c.302G>A) is very rare (popmax 0.00667%, afr) (gnomAD).

How is CACH syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AARS2 p.Arg101His (c.302G>A)?

AlphaMissense predicts likely benign (score 0.1739) — an in-silico prediction, not a clinical call.

AARS2 p.Arg101His

c.302G>A · rs545566267 · VCV812989

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1739 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy, progressive, with ovarian failure

Computational evidence

Protein change
AlphaMissense	0.1739	likely benign
REVEL	0.876	moderately pathogenic-leaning
SaProt	LLR -10.46	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.00019 · regional, not allelic
Overall
CADD	33.0	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 0.00667% African / African-American · 5/74,932 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000434% 7/1,614,008 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,986
South Asian	0.0022%	45,547

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.Arg101His
Coding: c.302G>A
MANE Select: NM_020745
dbSNP: rs545566267
Type: single nucleotide variant
Location: chr6:44312205 (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

Disease context

leukoencephalopathy, progressive, with ovarian failure — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CACH syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

AARS2 p.Arg101Cys Uncertain significance ★ ⚠ same residue
AARS2 p.Arg199Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AARS2 p.Arg521Ter Pathogenic ★★ same condition
AARS2 p.Arg592Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
AARS2 p.Arg958Ter Pathogenic/Likely pathogenic ★★ same condition
AARS2 p.Thr782Ile Likely pathogenic ★★ same condition
AARS2 p.Ala386Val Uncertain significance ★★ ⚠ same condition
AARS2 p.Gly965Arg 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/aars2-p-arg101his (accessed [today's date]).

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