Is YARS1 p.Pro399= (c.1197A>G) pathogenic?

YARS1 p.Pro399= (c.1197A>G) is classified Likely benign in YARS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-14). Very rare (popmax 0.0011%, sas); Associated with Charcot-Marie-Tooth disease dominant intermediate C.

What condition is associated with YARS1 p.Pro399= (c.1197A>G)?

YARS1 p.Pro399= (c.1197A>G) is associated with Charcot-Marie-Tooth disease dominant intermediate C (ClinVar).

How common is YARS1 p.Pro399= (c.1197A>G) in the general population?

YARS1 p.Pro399= (c.1197A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

YARS1 p.Pro399=

Q: How is Autosomal dominant intermediate Charcot-Marie-Tooth disease type C inherited?

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

c.1197A>G · rs768603403 · VCV1681491

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Charcot-Marie-Tooth disease dominant intermediate C

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.1	GERP -4.5
Overall
CADD	4.426	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,614,022 alleles · very rare exomes 10/1,461,878 · genomes 1/152,144 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	0.000847%	118,004

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: YARS1
Protein: p.Pro399=
Coding: c.1197A>G
MANE Select: NM_003680
dbSNP: rs768603403
Type: single nucleotide variant
Location: chr1:32780222 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.12 · 8 PDB
Residue 399: the trna-binding domain

Full YARS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease dominant intermediate C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant intermediate Charcot-Marie-Tooth disease type C (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

YARS1 p.Pro399Ser Uncertain significance ★ ⚠ same residue
YARS1 p.Glu196Gln Pathogenic/Likely pathogenic ★★ same condition
YARS1 p.Glu196Lys Pathogenic/Likely pathogenic ★★ same condition
YARS1 p.Pro167Thr Pathogenic/Likely pathogenic ★★ same condition
YARS1 c.1042+3A>C Uncertain significance ★★ same condition
YARS1 c.58-2A>G Uncertain significance ★★ same condition
YARS1 c.*539A>G Uncertain significance ★★ same condition
YARS1 p.Ala181Asp 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/yars1-p-pro399 (accessed [today's date]).

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