Is PKLR p.Arg504Leu (c.1511G>T) pathogenic?

PKLR p.Arg504Leu (c.1511G>T) is classified Likely pathogenic in PKLR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-03). AlphaMissense: likely pathogenic (0.7648); Very rare (popmax 0.00333%, amr); Associated with pyruvate kinase deficiency of red cells.

What condition is associated with PKLR p.Arg504Leu (c.1511G>T)?

PKLR p.Arg504Leu (c.1511G>T) is associated with pyruvate kinase deficiency of red cells (ClinVar).

How common is PKLR p.Arg504Leu (c.1511G>T) in the general population?

PKLR p.Arg504Leu (c.1511G>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PKLR p.Arg504Leu (c.1511G>T)?

AlphaMissense predicts likely pathogenic (score 0.7648) — an in-silico prediction, not a clinical call.

PKLR p.Arg504Leu

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.1511G>T · rs185753709 · VCV2431446

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate kinase deficiency of red cells

Computational evidence

Protein change
AlphaMissense	0.7648	likely pathogenic ✓ concordant with ClinVar
REVEL	0.956	strongly pathogenic-leaning
SaProt	LLR -14.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 2,951 bp · p 2.2e-05 · regional, not allelic
Overall
CADD	28.6	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 0.00333% Admixed American · 2/60,014 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,980 alleles · very rare exomes 0/1,461,762 · genomes 2/152,218 · 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.Arg504Leu
Coding: c.1511G>T
MANE Select: NM_000298
dbSNP: rs185753709
Type: single nucleotide variant
Location: chr1:155291863 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 504: a UniProt-annotated variant site (in cnsha2; instability of the protein); 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.Arg504His Likely pathogenic ★ same residue
PKLR p.Arg504Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg504leu (accessed [today's date]).

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