Is NDP p.Arg2Ile (c.5G>T) pathogenic?

NDP p.Arg2Ile (c.5G>T) is classified Likely benign in NDP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-02). AlphaMissense: likely benign (0.2901); Very rare (popmax 0.000224%, nfe).

How common is NDP p.Arg2Ile (c.5G>T) in the general population?

NDP p.Arg2Ile (c.5G>T) is very rare (popmax 0.000224%, nfe) (gnomAD).

What do computational predictors say about NDP p.Arg2Ile (c.5G>T)?

AlphaMissense predicts likely benign (score 0.2901) — an in-silico prediction, not a clinical call.

NDP p.Arg2Ile

c.5G>T · rs369355373 · VCV1113955

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2901 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000224%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2901	likely benign
REVEL	0.443	indeterminate
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 0.81, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 8,843 bp · p 0.0055 · regional, not allelic
Overall
CADD	18.67	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 0.000224% European (non-Finnish) · 2/894,320 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.00347% 42/1,209,206 alleles · very rare exomes 40/1,096,991 · genomes 2/112,215 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.159%	629
Remaining individualsnot grpmax-eligible	0.0105%	9,512
European (non-Finnish)grpmax	0.000224%	447,159

Ashkenazi Jewish 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: NDP
Protein: p.Arg2Ile
Coding: c.5G>T
MANE Select: NM_000266
dbSNP: rs369355373
Type: single nucleotide variant
Location: chrX:43958641 (GRCh38)
Structure: AlphaFold pLDDT 83.92 · 12 PDB

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

Similar variants

NDP p.Ala118Asp Pathogenic/Likely pathogenic ★★ same type
NDP p.Arg109Ter Pathogenic ★★ same type
NDP p.Arg115Ter Pathogenic ★★ same type
NDP p.Arg121Trp Pathogenic/Likely pathogenic ★★ same type
NDP p.Arg37Ter Pathogenic/Likely pathogenic ★★ same type
NDP p.Arg38Cys Pathogenic ★★ same type
NDP p.Arg74Cys Pathogenic ★★ same type
NDP p.Cys110Phe Likely pathogenic ★★ same type

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/ndp-p-arg2ile (accessed [today's date]).

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