Is AARS1 p.Pro234Ser (c.700C>T) pathogenic?

AARS1 p.Pro234Ser (c.700C>T) is classified Benign/Likely benign in AARS1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-06-01). AlphaMissense: ambiguous (0.3625); Rare (popmax 0.858%, mid); Associated with leukoencephalopathy, hereditary diffuse, with spheroids 2.

What condition is associated with AARS1 p.Pro234Ser (c.700C>T)?

AARS1 p.Pro234Ser (c.700C>T) is associated with leukoencephalopathy, hereditary diffuse, with spheroids 2, Charcot-Marie-Tooth disease axonal type 2N, developmental and epileptic encephalopathy, 29 (ClinVar).

How common is AARS1 p.Pro234Ser (c.700C>T) in the general population?

AARS1 p.Pro234Ser (c.700C>T) is rare (popmax 0.858%, mid) (gnomAD).

What do computational predictors say about AARS1 p.Pro234Ser (c.700C>T)?

AlphaMissense predicts ambiguous (score 0.3625) — an in-silico prediction, not a clinical call.

AARS1 p.Pro234Ser

c.700C>T · rs141840552 · VCV216549

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.3625 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.858%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

leukoencephalopathy, hereditary diffuse, with spheroids 2

Computational evidence

Protein change
AlphaMissense	0.3625	ambiguous
REVEL	0.722	pathogenic-leaning
SaProt	LLR -12.33	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.73, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.25 · regional, not allelic
Overall
CADD	27.0	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 0.858% Middle Eastern · 52/6,062 alleles

Filtering AF 0.672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.605%

Overall 0.158% 2,557/1,614,158 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.858%	117
Admixed American	0.368%	272
South Asian	0.312%	321
Remaining individualsnot grpmax-eligible	0.2%	500
European (non-Finnish)	0.153%	652
Ashkenazi Jewishnot grpmax-eligible	0.0709%	1,410
African / African-American	0.0507%	1,974
Finnishnot grpmax-eligible	0.00781%	12,809
East Asian	0.00223%	44,876

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: AARS1
Protein: p.Pro234Ser
Coding: c.700C>T
MANE Select: NM_001605
dbSNP: rs141840552
Type: single nucleotide variant
Location: chr16:70270312 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 90.66 · 10 PDB
Residue 234: a β-strand

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: Charcot-Marie-Tooth disease axonal type 2N developmental and epileptic encephalopathy, 29 Charcot-Marie-Tooth disease type 2 trichothiodystrophy 8, nonphotosensitive

Similar variants

AARS1 p.Pro234Arg Uncertain significance ★ ⚠ same residue
AARS1 c.2177+1G>A Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg13Ter Pathogenic ★★ same condition
AARS1 p.Arg246Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg329Cys Likely pathogenic ★★ same condition
AARS1 p.Arg329His Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg330Ter Pathogenic/Likely pathogenic ★★ same condition
AARS1 p.Arg333Ter 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/aars1-p-pro234ser (accessed [today's date]).

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