Is PKLR p.Arg559Pro (c.1676G>C) pathogenic?

PKLR p.Arg559Pro (c.1676G>C) is classified Likely pathogenic in PKLR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-26). AlphaMissense: likely pathogenic (0.8898); Absent from gnomAD v4.1.

How common is PKLR p.Arg559Pro (c.1676G>C) in the general population?

PKLR p.Arg559Pro (c.1676G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PKLR p.Arg559Pro (c.1676G>C)?

AlphaMissense predicts likely pathogenic (score 0.8898) — an in-silico prediction, not a clinical call.

PKLR p.Arg559Pro

c.1676G>C · rs1456158956 · VCV2683181

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8898 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8898	likely pathogenic ✓ concordant with ClinVar
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -14.92	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 2.7	GERP 1.2, phastCons 0.99
Regional constraint	o/e 0.73	unconstrained · MANE · 2,951 bp · p 2.2e-05 · regional, not allelic
Overall
CADD	25.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PKLR
Protein: p.Arg559Pro
Coding: c.1676G>C
MANE Select: NM_000298
dbSNP: rs1456158956
Type: single nucleotide variant
Location: chr1:155290621 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 559: a UniProt-annotated variant site (in cnsha2); a binding site; a β-strand

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

Similar variants

PKLR p.Arg559= Pathogenic ★ same residue
PKLR p.Arg559Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
PKLR p.Arg559Ter Conflicting classifications of pathogenicity ★ same residue
PKLR p.Arg559fs Pathogenic ★ same residue
PKLR c.101-1G>A Pathogenic ★★ same type
PKLR c.1116+2T>G Pathogenic ★★ same type
PKLR c.1618+1G>A Likely pathogenic ★★ same type
PKLR c.694+2T>G Pathogenic/Likely pathogenic ★★ same type

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-arg559pro (accessed [today's date]).

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