Is NMBR p.Val97Asp (c.290T>A) pathogenic?

NMBR p.Val97Asp (c.290T>A) is classified Uncertain significance in NMBR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). AlphaMissense: likely pathogenic (0.9848); Ultra-rare (popmax 0.0483%, sas).

How common is NMBR p.Val97Asp (c.290T>A) in the general population?

NMBR p.Val97Asp (c.290T>A) is ultra-rare (popmax 0.0483%, sas) (gnomAD).

What do computational predictors say about NMBR p.Val97Asp (c.290T>A)?

AlphaMissense predicts likely pathogenic (score 0.9848) — an in-silico prediction, not a clinical call.

NMBR p.Val97Asp

c.290T>A · rs373070325 · VCV3200775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9848 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9848	likely pathogenic · top 3% in NMBR
REVEL	0.559	indeterminate
SaProt	LLR -14.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 0.74, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00021 · regional, not allelic
Overall
CADD	28.8	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 0.0483% South Asian · 44/91,080 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.016% 258/1,614,006 alleles · ultra-rare exomes 245/1,461,878 · genomes 13/152,128 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0483%	2,070
European (non-Finnish)	0.0168%	5,960
Remaining individualsnot grpmax-eligible	0.0144%	6,942
Finnishnot grpmax-eligible	0.00469%	21,344
Admixed American	0.00333%	29,998
African / African-American	0.00267%	37,457

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.Val97Asp
Coding: c.290T>A
MANE Select: NM_002511
dbSNP: rs373070325
Type: single nucleotide variant
Location: chr6:142088369 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 2 PDB
Residue 97: an α-helix

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

Similar variants

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
NMBR p.Ala32Gly 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-val97asp (accessed [today's date]).

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