Is PKLR p.Arg486Trp (c.1456C>T) pathogenic?

PKLR p.Arg486Trp (c.1456C>T) is classified Pathogenic/Likely pathogenic in PKLR (ClinVar, Multiple submitters, 33 submitters; last evaluated 2026-02-23). AlphaMissense: ambiguous (0.36); Rare (popmax 0.583%, mid); Associated with PKLR-related disorder.

What condition is associated with PKLR p.Arg486Trp (c.1456C>T)?

PKLR p.Arg486Trp (c.1456C>T) is associated with PKLR-related disorder, pyruvate kinase hyperactivity, pyruvate kinase deficiency of red cells (ClinVar).

How common is PKLR p.Arg486Trp (c.1456C>T) in the general population?

PKLR p.Arg486Trp (c.1456C>T) is rare (popmax 0.583%, mid) (gnomAD).

What do computational predictors say about PKLR p.Arg486Trp (c.1456C>T)?

AlphaMissense predicts ambiguous (score 0.36) — an in-silico prediction, not a clinical call.

PKLR p.Arg486Trp

c.1456C>T · rs116100695 · VCV1513

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 33 submitters

AlphaMissense

ambiguous

0.36 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.583%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

PKLR-related disorder

Computational evidence

Protein change
AlphaMissense	0.36	ambiguous
REVEL	0.914	moderately pathogenic-leaning
SaProt	LLR -13.61	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.79 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 2,951 bp · p 2.2e-05 · regional, not allelic
Overall
CADD	34.0	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 0.583% Middle Eastern · 32/5,488 alleles

Filtering AF 0.424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.37%

Overall 0.295% 4,766/1,613,440 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.778%	129
Middle Easterngrpmax	0.583%	172
South Asian	0.38%	263
Ashkenazi Jewishnot grpmax-eligible	0.317%	315
Remaining individualsnot grpmax-eligible	0.303%	330
European (non-Finnish)	0.29%	345
Admixed American	0.24%	417
African / African-American	0.0547%	1,830
East Asian	0.00223%	44,882

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg486Trp
Coding: c.1456C>T
MANE Select: NM_000298
dbSNP: rs116100695
Type: single nucleotide variant
Location: chr1:155291918 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 486: a UniProt-annotated variant site (in cnsha2; no conformational change)

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

Disease context

PKLR-related disorder

Also linked: pyruvate kinase hyperactivity pyruvate kinase deficiency of red cells

Similar variants

PKLR p.Arg486Gln Uncertain significance ★★ ⚠ same residue
PKLR c.1116+2T>G Pathogenic ★★ same condition
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.Ala495Val 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-arg486trp (accessed [today's date]).

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