Is NDRG1 p.Pro298Leu (c.893C>T) pathogenic?

NDRG1 p.Pro298Leu (c.893C>T) is classified Uncertain significance in NDRG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-31). AlphaMissense: likely pathogenic (0.9888); Very rare (popmax 0.00167%, amr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with NDRG1 p.Pro298Leu (c.893C>T)?

NDRG1 p.Pro298Leu (c.893C>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is NDRG1 p.Pro298Leu (c.893C>T) in the general population?

NDRG1 p.Pro298Leu (c.893C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about NDRG1 p.Pro298Leu (c.893C>T)?

AlphaMissense predicts likely pathogenic (score 0.9888) — an in-silico prediction, not a clinical call.

NDRG1 p.Pro298Leu

c.893C>T · rs753836263 · VCV410956

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9888 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.9888	likely pathogenic
REVEL	0.785	moderately pathogenic-leaning
SaProt	LLR -15.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.77 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 45 kb · p 0.097 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,030 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00041% 6/1,461,872 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,255
Admixed Americangrpmax	0.00167%	60,030
European (non-Finnish)	0.000254%	393,342

Remaining individuals 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: NDRG1
Protein: p.Pro298Leu
Coding: c.893C>T
MANE Select: NM_006096
dbSNP: rs753836263
Type: single nucleotide variant
Location: chr8:133242073 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 1 PDB
Residue 298: an α-helix

Full NDRG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NDRG1 p.Pro298Ser Uncertain significance ★ ⚠ same residue
NDRG1 p.Pro298= Likely benign ★ same residue
NDRG1 c.205+1G>A Pathogenic/Likely pathogenic ★★ same condition
NDRG1 c.205+1G>C Pathogenic/Likely pathogenic ★★ same condition
NDRG1 p.Arg148Ter Pathogenic ★★ same condition
NDRG1 p.Lys14Ter Pathogenic/Likely pathogenic ★★ same condition
NDRG1 c.595-6A>G Uncertain significance ★★ same condition
NDRG1 c.699-3C>T 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/ndrg1-p-pro298leu (accessed [today's date]).

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