Is YARS1 p.Pro331Arg (c.992C>G) pathogenic?

YARS1 p.Pro331Arg (c.992C>G) is classified Uncertain significance in YARS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-27). AlphaMissense: likely benign (0.2032); Very rare (popmax 8.47e-05%, nfe); Associated with Charcot-Marie-Tooth disease dominant intermediate C.

What condition is associated with YARS1 p.Pro331Arg (c.992C>G)?

YARS1 p.Pro331Arg (c.992C>G) is associated with Charcot-Marie-Tooth disease dominant intermediate C (ClinVar).

How common is YARS1 p.Pro331Arg (c.992C>G) in the general population?

YARS1 p.Pro331Arg (c.992C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about YARS1 p.Pro331Arg (c.992C>G)?

AlphaMissense predicts likely benign (score 0.2032) — an in-silico prediction, not a clinical call.

YARS1 p.Pro331Arg

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.992C>G · rs2523359388 · VCV2832298

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2032 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease dominant intermediate C

Computational evidence

Protein change
AlphaMissense	0.2032	likely benign
REVEL	0.525	indeterminate
SaProt	LLR -13.07	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 41 kb · p 4.7e-06 · regional, not allelic
Overall
CADD	25.4	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 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.2e-05% 1/1,614,102 alleles · very rare exomes 1/1,461,856 · genomes 0/152,246 · joint denominator

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.Pro331Arg
Coding: c.992C>G
MANE Select: NM_003680
dbSNP: rs2523359388
Type: single nucleotide variant
Location: chr1:32782454 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.12 · 8 PDB
Residue 331: an α-helix

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.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
YARS1 p.Ala384Thr 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-pro331arg (accessed [today's date]).

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