Is NMBR p.Arg289Trp (c.865C>T) pathogenic?

NMBR p.Arg289Trp (c.865C>T) is classified Uncertain significance in NMBR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: ambiguous (0.4574); Ultra-rare (popmax 0.0361%, afr).

How common is NMBR p.Arg289Trp (c.865C>T) in the general population?

NMBR p.Arg289Trp (c.865C>T) is ultra-rare (popmax 0.0361%, afr) (gnomAD).

What do computational predictors say about NMBR p.Arg289Trp (c.865C>T)?

AlphaMissense predicts ambiguous (score 0.4574) — an in-silico prediction, not a clinical call.

NMBR p.Arg289Trp

c.865C>T · VCV3920441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4574 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0361%, afr)

Computational evidence

Protein change
AlphaMissense	0.4574	ambiguous
REVEL	0.556	indeterminate
SaProt	LLR -9.33	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2	GERP -1.3, phastCons 0.98
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00021 · regional, not allelic
Overall
CADD	25.2	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 0.0361% African / African-American · 27/74,892 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00304% 49/1,613,712 alleles · ultra-rare exomes 25/1,461,592 · genomes 24/152,120 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0361%	2,774
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,588
Admixed American	0.00334%	29,982
Remaining individualsnot grpmax-eligible	0.0032%	31,239
East Asian	0.00223%	44,872
European (non-Finnish)	0.00136%	73,740

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: NMBR
Protein: p.Arg289Trp
Coding: c.865C>T
MANE Select: NM_002511
Type: single nucleotide variant
Location: chr6:142075956 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 2 PDB
Residue 289: an α-helix

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

Similar variants

NMBR p.Arg289Gln Uncertain significance ★ ⚠ same residue
NMBR p.Arg310Trp Likely benign ★★ same type
NMBR p.Ile46= Benign/Likely benign ★★ same type
NMBR p.Ser358= Likely benign ★★ same type
NMBR p.Ala136Asp Uncertain significance ★ ⚠ same type
NMBR p.Ala179Val Uncertain significance ★ ⚠ same type
NMBR p.Ala185Val Uncertain significance ★ ⚠ same type
NMBR p.Ala236Thr Uncertain significance ★ ⚠ 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/nmbr-p-arg289trp (accessed [today's date]).

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