Is NDRG1 p.Ser2Pro (c.4T>C) pathogenic?

NDRG1 p.Ser2Pro (c.4T>C) is classified Uncertain significance in NDRG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-25). AlphaMissense: likely benign (0.1158); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with NDRG1 p.Ser2Pro (c.4T>C)?

NDRG1 p.Ser2Pro (c.4T>C) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is NDRG1 p.Ser2Pro (c.4T>C) in the general population?

NDRG1 p.Ser2Pro (c.4T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NDRG1 p.Ser2Pro (c.4T>C)?

AlphaMissense predicts likely benign (score 0.1158) — an in-silico prediction, not a clinical call.

NDRG1 p.Ser2Pro

c.4T>C · rs781381539 · VCV581450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1158 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.1158	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -7.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.6	GERP 0.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 45 kb · p 0.097 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NDRG1
Protein: p.Ser2Pro
Coding: c.4T>C
MANE Select: NM_006096
dbSNP: rs781381539
Type: single nucleotide variant
Location: chr8:133284308 (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 2: a modified residue (phosphoserine); a modified residue (n-acetylserine)

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.Ser2Ala Uncertain significance ★★ ⚠ same residue
NDRG1 p.Ser2= 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-ser2pro (accessed [today's date]).

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