Is PKLR p.Arg103fs (c.307del) pathogenic?

PKLR p.Arg103fs (c.307del) is classified Pathogenic/Likely pathogenic in PKLR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-16). Very rare (popmax 0.00167%, amr); Associated with pyruvate kinase deficiency of red cells.

What condition is associated with PKLR p.Arg103fs (c.307del)?

PKLR p.Arg103fs (c.307del) is associated with pyruvate kinase deficiency of red cells (ClinVar).

How common is PKLR p.Arg103fs (c.307del) in the general population?

PKLR p.Arg103fs (c.307del) is very rare (popmax 0.00167%, amr) (gnomAD).

PKLR p.Arg103fs

Q: How is Hemolytic anemia due to red cell pyruvate kinase deficiency inherited?

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

c.307del · rs1433205059 · VCV1163647

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

pyruvate kinase deficiency of red cells

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.3	GERP -4.2, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,010 alleles

Overall 0.000657% 1/152,182 alleles · very rare

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: PKLR
Protein: p.Arg103fs
Coding: c.307del
MANE Select: NM_000298
dbSNP: rs1433205059
Type: Deletion
Location: chr1:155295733 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 103: an α-helix

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

Disease context

pyruvate kinase deficiency of red cells — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hemolytic anemia due to red cell pyruvate kinase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

PKLR p.Ile131del Pathogenic/Likely pathogenic ★★ same condition
PKLR p.Val276fs Pathogenic ★★ same condition
PKLR c.1618+1del Pathogenic ★ same condition
PKLR p.Arg135fs Pathogenic ★ same condition
PKLR p.Asp339fs Pathogenic ★ same condition
PKLR p.Phe350fs Likely pathogenic ★ same condition
PKLR p.Arg103Ser Uncertain significance ★ ⚠ same residue
PKLR p.Asp220_Leu226del 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/pklr-p-arg103fs (accessed [today's date]).

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