Is NADK2 p.Pro31= (c.93C>A) pathogenic?

NADK2 p.Pro31= (c.93C>A) is classified Likely benign in NADK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). Very rare (popmax 0.00496%, amr); Associated with progressive encephalopathy with leukodystrophy due to DECR deficiency.

What condition is associated with NADK2 p.Pro31= (c.93C>A)?

NADK2 p.Pro31= (c.93C>A) is associated with progressive encephalopathy with leukodystrophy due to DECR deficiency (ClinVar).

How common is NADK2 p.Pro31= (c.93C>A) in the general population?

NADK2 p.Pro31= (c.93C>A) is very rare (popmax 0.00496%, amr) (gnomAD).

NADK2 p.Pro31=

Q: How is Progressive encephalopathy with leukodystrophy due to DECR deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.93C>A · VCV4799042

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00496%, amr)

Conditions

progressive encephalopathy with leukodystrophy due to DECR deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.007	GERP -3, phastCons 0.004
Overall
CADD	10.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00496% Admixed American · 1/20,172 alleles

Overall 0.000176% 2/1,133,580 alleles · very rare exomes 1/984,740 · genomes 1/148,840 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00496%	20,172
European (non-Finnish)	0.000108%	928,928

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: NADK2
Protein: p.Pro31=
Coding: c.93C>A
MANE Select: NM_001085411
Type: single nucleotide variant
Location: chr5:36241706 (GRCh38)
Gene constraint: LOEUF 0.927 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.13 · 5 PDB
Residue 31: the 'disordered' region

Full NADK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

progressive encephalopathy with leukodystrophy due to DECR deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Progressive encephalopathy with leukodystrophy due to DECR deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

NADK2 c.1190+6C>T Uncertain significance ★★ same condition
NADK2 p.Arg130Trp Uncertain significance ★★ ⚠ same condition
NADK2 p.Arg137Cys Uncertain significance ★★ ⚠ same condition
NADK2 p.Arg137His Uncertain significance ★★ ⚠ same condition
NADK2 p.Arg150Gln Uncertain significance ★★ ⚠ same condition
NADK2 p.Arg197Gln Uncertain significance ★★ ⚠ same condition
NADK2 p.Arg250Thr Uncertain significance ★★ ⚠ same condition
NADK2 p.Arg261Ser Uncertain significance ★★ ⚠ 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/nadk2-p-pro31 (accessed [today's date]).

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