Is PKLR p.Arg498Ser (c.1492C>A) pathogenic?

PKLR p.Arg498Ser (c.1492C>A) is classified Likely pathogenic in PKLR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). AlphaMissense: likely pathogenic (0.7891); Very rare (popmax 0.0022%, sas); Associated with pyruvate kinase deficiency of red cells.

What condition is associated with PKLR p.Arg498Ser (c.1492C>A)?

PKLR p.Arg498Ser (c.1492C>A) is associated with pyruvate kinase deficiency of red cells (ClinVar).

How common is PKLR p.Arg498Ser (c.1492C>A) in the general population?

PKLR p.Arg498Ser (c.1492C>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about PKLR p.Arg498Ser (c.1492C>A)?

AlphaMissense predicts likely pathogenic (score 0.7891) — an in-silico prediction, not a clinical call.

PKLR p.Arg498Ser

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.1492C>A · VCV3341366

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate kinase deficiency of red cells

Computational evidence

Protein change
AlphaMissense	0.7891	likely pathogenic ✓ concordant with ClinVar
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -10.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.26	acceptor loss, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	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	28.4	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 0.0022% South Asian · 2/91,070 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,964 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.Arg498Ser
Coding: c.1492C>A
MANE Select: NM_000298
Type: single nucleotide variant
Location: chr1:155291882 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 498: a UniProt-annotated variant site (in cnsha2); a β-strand

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.Arg498Cys Likely pathogenic ★ same residue
PKLR p.Arg498His Conflicting classifications of pathogenicity ★ ⚠ same residue
PKLR p.Arg498= Likely benign ★ 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

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-arg498ser (accessed [today's date]).

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