Is YARS2 p.Phe159= (c.477C>T) pathogenic?

YARS2 p.Phe159= (c.477C>T) is classified Conflicting classifications of pathogenicity in YARS2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-27). Rare (popmax 0.512%, mid); Associated with myopathy, lactic acidosis, and sideroblastic anemia 2.

What condition is associated with YARS2 p.Phe159= (c.477C>T)?

YARS2 p.Phe159= (c.477C>T) is associated with myopathy, lactic acidosis, and sideroblastic anemia 2 (ClinVar).

How common is YARS2 p.Phe159= (c.477C>T) in the general population?

YARS2 p.Phe159= (c.477C>T) is rare (popmax 0.512%, mid) (gnomAD).

YARS2 p.Phe159=

Q: How is Mitochondrial myopathy and sideroblastic anemia inherited?

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

c.477C>T · rs774325742 · VCV308462

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.512%, mid)

Conditions

myopathy, lactic acidosis, and sideroblastic anemia 2

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 2	phastCons 0.98
Overall
CADD	6.538	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.512% Middle Eastern · 31/6,058 alleles

Filtering AF 0.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.322%

Overall 0.00533% 86/1,613,864 alleles · rare exomes 76/1,461,516 · genomes 10/152,348 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.512%	195
Admixed American	0.03%	3,335
Remaining individualsnot grpmax-eligible	0.0128%	7,813
South Asian	0.00329%	30,362
European (non-Finnish)	0.00212%	47,201
African / African-American	0.00133%	75,074

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: YARS2
Protein: p.Phe159=
Coding: c.477C>T
MANE Select: NM_001040436
dbSNP: rs774325742
Type: single nucleotide variant
Location: chr12:32755398 (GRCh38)
Gene constraint: LOEUF 1.035 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.57 · 2 PDB

Full YARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myopathy, lactic acidosis, and sideroblastic anemia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial myopathy and sideroblastic anemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy

Similar variants

YARS2 p.Asp311Glu Pathogenic/Likely pathogenic ★★ ⚠ same condition
YARS2 p.Glu212Ter Pathogenic/Likely pathogenic ★★ same condition
YARS2 p.Ile251Val Likely pathogenic ★★ ⚠ same condition
YARS2 p.Phe52Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
YARS2 p.Ser33Ter Pathogenic/Likely pathogenic ★★ same condition
YARS2 p.Arg414His Uncertain significance ★★ ⚠ same condition
YARS2 p.Met428Lys Uncertain significance ★★ same condition
YARS2 c.1103+18T>C Benign ★★ 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/yars2-p-phe159 (accessed [today's date]).

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