Is YARS1 p.Phe488= (c.1464C>T) pathogenic?

YARS1 p.Phe488= (c.1464C>T) is classified Conflicting classifications of pathogenicity in YARS1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-27). Ultra-rare (popmax 0.0395%, sas); Associated with Charcot-Marie-Tooth disease dominant intermediate C.

What condition is associated with YARS1 p.Phe488= (c.1464C>T)?

YARS1 p.Phe488= (c.1464C>T) is associated with Charcot-Marie-Tooth disease dominant intermediate C (ClinVar).

How common is YARS1 p.Phe488= (c.1464C>T) in the general population?

YARS1 p.Phe488= (c.1464C>T) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

YARS1 p.Phe488=

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.1464C>T · rs780574093 · VCV194050

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, 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 0.6	GERP -3.6, phastCons 0.91
Overall
CADD	10.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0395% South Asian · 36/91,090 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00446% 72/1,614,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
East Asian	0.00668%	14,965
African / African-American	0.004%	24,971
European (non-Finnish)	0.00237%	42,144
Admixed American	0.00167%	59,984
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Phe488=
Coding: c.1464C>T
MANE Select: NM_003680
dbSNP: rs780574093
Type: single nucleotide variant
Location: chr1:32779394 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.12 · 8 PDB
Residue 488: 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.Phe488Leu 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-phe488 (accessed [today's date]).

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