Is AARS1 p.Cys152Phe (c.455G>T) pathogenic?

AARS1 p.Cys152Phe (c.455G>T) is classified Pathogenic/Likely pathogenic in AARS1 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2023-10-18). AlphaMissense: likely pathogenic (0.9671); Absent from gnomAD v4.1; Associated with leukoencephalopathy, hereditary diffuse, with spheroids 2.

What condition is associated with AARS1 p.Cys152Phe (c.455G>T)?

AARS1 p.Cys152Phe (c.455G>T) is associated with leukoencephalopathy, hereditary diffuse, with spheroids 2, leukoencephalopathy, hereditary diffuse, with spheroids (ClinVar).

How common is AARS1 p.Cys152Phe (c.455G>T) in the general population?

AARS1 p.Cys152Phe (c.455G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AARS1 p.Cys152Phe (c.455G>T)?

AlphaMissense predicts likely pathogenic (score 0.9671) — an in-silico prediction, not a clinical call.

AARS1 p.Cys152Phe

c.455G>T · rs2152166694 · VCV1299470

Pathogenic/Likely pathogenic No assertion criteria

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9671 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy, hereditary diffuse, with spheroids 2

Computational evidence

Protein change
AlphaMissense	0.9671	likely pathogenic ✓ concordant with ClinVar
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -12.86	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	28.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AARS1
Protein: p.Cys152Phe
Coding: c.455G>T
MANE Select: NM_001605
dbSNP: rs2152166694
Type: single nucleotide variant
Location: chr16:70276510 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB
Residue 152: a UniProt-annotated variant site (in hdls2; uncertain significance); an α-helix

Full AARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukoencephalopathy, hereditary diffuse, with spheroids 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: leukoencephalopathy, hereditary diffuse, with spheroids

Similar variants

AARS1 p.Arg194Trp Uncertain significance ★★ ⚠ same condition
AARS1 p.Arg320His Uncertain significance ★★ ⚠ same condition
AARS1 p.Asn657Asp Uncertain significance ★★ ⚠ same condition
AARS1 p.Gln588His Uncertain significance ★★ ⚠ same condition
AARS1 c.1672-4T>A Benign/Likely benign ★★ same condition
AARS1 p.Lys967Met Benign/Likely benign ★★ same condition
AARS1 p.Pro234Ser Benign/Likely benign ★★ same condition
AARS1 p.Tyr468= Benign/Likely benign ★★ 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/aars1-p-cys152phe (accessed [today's date]).

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