Is PKLR p.Asp331Glu (c.993C>A) pathogenic?

PKLR p.Asp331Glu (c.993C>A) is classified Pathogenic/Likely pathogenic in PKLR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-07-06). AlphaMissense: likely pathogenic (0.8276); Ultra-rare (popmax 0.0383%, amr); Associated with PKLR-related disorder.

What condition is associated with PKLR p.Asp331Glu (c.993C>A)?

PKLR p.Asp331Glu (c.993C>A) is associated with PKLR-related disorder, pyruvate kinase deficiency of red cells (ClinVar).

How common is PKLR p.Asp331Glu (c.993C>A) in the general population?

PKLR p.Asp331Glu (c.993C>A) is ultra-rare (popmax 0.0383%, amr) (gnomAD).

What do computational predictors say about PKLR p.Asp331Glu (c.993C>A)?

AlphaMissense predicts likely pathogenic (score 0.8276) — an in-silico prediction, not a clinical call.

PKLR p.Asp331Glu

c.993C>A · rs138476691 · VCV1163643

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.8276 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PKLR-related disorder

Computational evidence

Protein change
AlphaMissense	0.8276	likely pathogenic ✓ concordant with ClinVar
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -8.67	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -4.3
Regional constraint	o/e 0.97	unconstrained · MANE · 7,868 bp · p 0.44 · regional, not allelic
Overall
CADD	12.0	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 0.0383% Admixed American · 23/59,982 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00985% 159/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0383%	2,608
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)	0.0108%	9,291

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.Asp331Glu
Coding: c.993C>A
MANE Select: NM_000298
dbSNP: rs138476691
Type: single nucleotide variant
Location: chr1:155294358 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 331: a β-strand; a UniProt-annotated variant site (in cnsha2; parma); 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

Also linked: pyruvate kinase deficiency of red cells

Similar variants

PKLR p.Asp331Asn Likely pathogenic ★★ same residue
PKLR p.Asp331= Likely benign ★★ 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

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-asp331glu (accessed [today's date]).

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