Is NMBR p.Val45Met (c.133G>A) pathogenic?

NMBR p.Val45Met (c.133G>A) is classified Uncertain significance in NMBR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: likely benign (0.1813); Ultra-rare (popmax 0.0708%, afr).

How common is NMBR p.Val45Met (c.133G>A) in the general population?

NMBR p.Val45Met (c.133G>A) is ultra-rare (popmax 0.0708%, afr) (gnomAD).

What do computational predictors say about NMBR p.Val45Met (c.133G>A)?

AlphaMissense predicts likely benign (score 0.1813) — an in-silico prediction, not a clinical call.

NMBR p.Val45Met

c.133G>A · rs146564973 · VCV2511172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1813 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0708%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1813	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -10.28	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00021 · regional, not allelic
Overall
CADD	25.3	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 0.0708% African / African-American · 53/74,906 alleles

Filtering AF 0.0555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0501%

Overall 0.00378% 61/1,613,948 alleles · ultra-rare exomes 33/1,461,860 · genomes 28/152,088 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0708%	1,413
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Admixed American	0.00333%	29,997
European (non-Finnish)	0.000169%	590,002

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.Val45Met
Coding: c.133G>A
MANE Select: NM_002511
dbSNP: rs146564973
Type: single nucleotide variant
Location: chr6:142088526 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 2 PDB
Residue 45: 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-val45met (accessed [today's date]).

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