Is NMBR p.Leu51Met (c.151C>A) pathogenic?

NMBR p.Leu51Met (c.151C>A) is classified Uncertain significance in NMBR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-26). AlphaMissense: likely benign (0.1346); Ultra-rare (popmax 0.0117%, nfe).

How common is NMBR p.Leu51Met (c.151C>A) in the general population?

NMBR p.Leu51Met (c.151C>A) is ultra-rare (popmax 0.0117%, nfe) (gnomAD).

What do computational predictors say about NMBR p.Leu51Met (c.151C>A)?

AlphaMissense predicts likely benign (score 0.1346) — an in-silico prediction, not a clinical call.

NMBR p.Leu51Met

c.151C>A · VCV3406312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1346 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1346	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -8.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.19, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00021 · regional, not allelic
Overall
CADD	18.95	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

Grpmax group 0.0117% European (non-Finnish) · 138/1,180,018 alleles

Filtering AF 0.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00948%

Overall 0.00892% 144/1,613,988 alleles · ultra-rare exomes 136/1,461,880 · genomes 8/152,108 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0117%	8,551
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00267%	37,455

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.Leu51Met
Coding: c.151C>A
MANE Select: NM_002511
Type: single nucleotide variant
Location: chr6:142088508 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 2 PDB
Residue 51: 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-leu51met (accessed [today's date]).

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