Is PKLR p.Ala128Pro (c.382G>C) pathogenic?

PKLR p.Ala128Pro (c.382G>C) is classified Uncertain significance in PKLR (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9162); Very rare (popmax 8.47e-05%, nfe); Associated with pyruvate kinase hyperactivity.

What condition is associated with PKLR p.Ala128Pro (c.382G>C)?

PKLR p.Ala128Pro (c.382G>C) is associated with pyruvate kinase hyperactivity, pyruvate kinase deficiency of red cells (ClinVar).

How common is PKLR p.Ala128Pro (c.382G>C) in the general population?

PKLR p.Ala128Pro (c.382G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PKLR p.Ala128Pro (c.382G>C)?

AlphaMissense predicts likely pathogenic (score 0.9162) — an in-silico prediction, not a clinical call.

PKLR p.Ala128Pro

c.382G>C · VCV3382420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9162 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyruvate kinase hyperactivity

Computational evidence

Protein change
AlphaMissense	0.9162	likely pathogenic
REVEL	0.771	pathogenic-leaning
SaProt	LLR -15.76	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 4.8	GERP 1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,868 bp · p 0.44 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,998 alleles

Overall 6.84e-05% 1/1,461,714 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.Ala128Pro
Coding: c.382G>C
MANE Select: NM_000298
Type: single nucleotide variant
Location: chr1:155295562 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 128: an α-helix

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

Disease context

pyruvate kinase hyperactivity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pyruvate kinase deficiency of red cells

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-ala128pro (accessed [today's date]).

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