Is NMBR p.Leu390Met (c.1168C>A) pathogenic?

NMBR p.Leu390Met (c.1168C>A) is classified Benign in NMBR (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-29). AlphaMissense: likely benign (0.0918); Common (popmax 22.2%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about NMBR p.Leu390Met (c.1168C>A)?

AlphaMissense predicts likely benign (score 0.0918) — an in-silico prediction, not a clinical call.

NMBR p.Leu390Met

Q: How common is NMBR p.Leu390Met (c.1168C>A) in the general population?

NMBR p.Leu390Met (c.1168C>A) is common (popmax 22.2%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1168C>A · rs7453944 · VCV1252678

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0918 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 22.2%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0918	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -8.90	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 1	GERP -0.068, phastCons 0.36
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00021 · regional, not allelic
Overall
CADD	21.0	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 22.2% Admixed American · 12,992/58,630 alleles

Filtering AF 21.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.7%

Overall 8.38% 134,201/1,602,362 alleles · common exomes 120,231/1,450,230 · genomes 13,970/152,132 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	22.2%	5
Finnishnot grpmax-eligible	10.7%	9
East Asian	10.5%	10
African / African-American	9.71%	10
Remaining individualsnot grpmax-eligible	8.2%	12
European (non-Finnish)	7.8%	13
South Asian	5.31%	19
Amishnot grpmax-eligible	4.39%	23
Ashkenazi Jewishnot grpmax-eligible	3.11%	32
Middle Eastern	2.17%	46

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.Leu390Met
Coding: c.1168C>A
MANE Select: NM_002511
dbSNP: rs7453944
Type: single nucleotide variant
Location: chr6:142075653 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 2 PDB
Residue 390: a UniProt-annotated variant site (in)

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-leu390met (accessed [today's date]).

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