Is YARS1 p.Pro399Ser (c.1195C>T) pathogenic?

YARS1 p.Pro399Ser (c.1195C>T) is classified Uncertain significance in YARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-22). AlphaMissense: likely benign (0.2458); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease dominant intermediate C.

What condition is associated with YARS1 p.Pro399Ser (c.1195C>T)?

YARS1 p.Pro399Ser (c.1195C>T) is associated with Charcot-Marie-Tooth disease dominant intermediate C (ClinVar).

How common is YARS1 p.Pro399Ser (c.1195C>T) in the general population?

YARS1 p.Pro399Ser (c.1195C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about YARS1 p.Pro399Ser (c.1195C>T)?

AlphaMissense predicts likely benign (score 0.2458) — an in-silico prediction, not a clinical call.

YARS1 p.Pro399Ser

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.1195C>T · rs2523351741 · VCV2031885

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2458 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease dominant intermediate C

Computational evidence

Protein change
AlphaMissense	0.2458	likely benign
REVEL	0.536	indeterminate
SaProt	LLR -14.38	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 41 kb · p 4.7e-06 · regional, not allelic
Overall
CADD	24.9	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: YARS1
Protein: p.Pro399Ser
Coding: c.1195C>T
MANE Select: NM_003680
dbSNP: rs2523351741
Type: single nucleotide variant
Location: chr1:32780224 (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.Pro399= Likely benign ★★ 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-pro399ser (accessed [today's date]).

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