Is PKLR p.Arg337Pro (c.1010G>C) pathogenic?

PKLR p.Arg337Pro (c.1010G>C) is classified Likely pathogenic in PKLR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-02-02). AlphaMissense: likely pathogenic (0.9967); Very rare (popmax 0.000169%, nfe); Associated with PKLR-related disorder.

What condition is associated with PKLR p.Arg337Pro (c.1010G>C)?

PKLR p.Arg337Pro (c.1010G>C) is associated with PKLR-related disorder (ClinVar).

How common is PKLR p.Arg337Pro (c.1010G>C) in the general population?

PKLR p.Arg337Pro (c.1010G>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about PKLR p.Arg337Pro (c.1010G>C)?

AlphaMissense predicts likely pathogenic (score 0.9967) — an in-silico prediction, not a clinical call.

PKLR p.Arg337Pro

c.1010G>C · rs1167329263 · VCV2631733

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PKLR-related disorder

Computational evidence

Protein change
AlphaMissense	0.9967	likely pathogenic ✓ concordant with ClinVar · top 1% in PKLR
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -13.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,868 bp · p 0.44 · regional, not allelic
Overall
CADD	32.0	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 0.000169% European (non-Finnish) · 2/1,179,996 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,112 alleles · very rare exomes 2/1,461,852 · genomes 0/152,260 · 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.Arg337Pro
Coding: c.1010G>C
MANE Select: NM_000298
dbSNP: rs1167329263
Type: single nucleotide variant
Location: chr1:155294341 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 337: an α-helix; a UniProt-annotated variant site (in cnsha2)

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

Disease context

PKLR-related disorder

Similar variants

PKLR p.Arg337Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PKLR p.Arg337= Likely benign ★ same residue
PKLR c.1116+2T>G Pathogenic ★★ same condition
PKLR p.Ala495Val Pathogenic ★★ ⚠ same condition
PKLR p.Arg479His Pathogenic ★★ ⚠ same condition
PKLR p.Arg486Trp Pathogenic/Likely pathogenic ★★ same condition
PKLR p.Arg510Gln Pathogenic ★★ ⚠ same condition
PKLR p.Arg510Ter 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-arg337pro (accessed [today's date]).

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