Is PKLR p.Pro303= (c.909G>C) pathogenic?

PKLR p.Pro303= (c.909G>C) is classified Conflicting classifications of pathogenicity in PKLR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-22). Very rare (popmax 0.00356%, nfe); Associated with pyruvate kinase deficiency of red cells.

What condition is associated with PKLR p.Pro303= (c.909G>C)?

PKLR p.Pro303= (c.909G>C) is associated with pyruvate kinase deficiency of red cells (ClinVar).

How common is PKLR p.Pro303= (c.909G>C) in the general population?

PKLR p.Pro303= (c.909G>C) is very rare (popmax 0.00356%, nfe) (gnomAD).

PKLR p.Pro303=

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.909G>C · rs200840994 · VCV292811

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Conditions

pyruvate kinase deficiency of red cells

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 -20	GERP -4.3
Overall
CADD	0.289	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 42/1,180,046 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.0026% 42/1,614,108 alleles · very rare exomes 38/1,461,876 · genomes 4/152,232 · 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: PKLR
Protein: p.Pro303=
Coding: c.909G>C
MANE Select: NM_000298
dbSNP: rs200840994
Type: single nucleotide variant
Location: chr1:155294538 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 303: 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 c.1618+1G>A Likely pathogenic ★★ same condition
PKLR c.694+2T>G Pathogenic/Likely pathogenic ★★ same condition
PKLR p.Ala423= Pathogenic/Likely pathogenic ★★ same condition
PKLR p.Arg270Ter Pathogenic ★★ same condition
PKLR p.Arg479His Pathogenic ★★ ⚠ same condition
PKLR p.Arg486Trp Pathogenic/Likely pathogenic ★★ same condition
PKLR p.Arg488Ter Pathogenic ★★ same condition
PKLR p.Arg504Leu Likely pathogenic ★★ 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-pro303 (accessed [today's date]).

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