Is NMBR p.Pro148Ala (c.442C>G) pathogenic?

NMBR p.Pro148Ala (c.442C>G) is classified Uncertain significance in NMBR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely pathogenic (0.629); Ultra-rare (popmax 0.0561%, nfe).

How common is NMBR p.Pro148Ala (c.442C>G) in the general population?

NMBR p.Pro148Ala (c.442C>G) is ultra-rare (popmax 0.0561%, nfe) (gnomAD).

What do computational predictors say about NMBR p.Pro148Ala (c.442C>G)?

AlphaMissense predicts likely pathogenic (score 0.629) — an in-silico prediction, not a clinical call.

NMBR p.Pro148Ala

c.442C>G · rs148202124 · VCV2273810

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0561%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.629	likely pathogenic
REVEL	0.651	pathogenic-leaning
SaProt	LLR -10.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00021 · regional, not allelic
Overall
CADD	26.6	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 0.0561% European (non-Finnish) · 661/1,179,122 alleles

Filtering AF 0.0525% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0511%

Overall 0.0473% 763/1,612,236 alleles · ultra-rare exomes 712/1,460,864 · genomes 51/151,372 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.142%	704
European (non-Finnish)grpmax	0.0561%	1,784
Remaining individualsnot grpmax-eligible	0.0416%	2,401
Admixed American	0.0384%	2,601
Middle Eastern	0.0165%	6,058
African / African-American	0.0121%	8,295
Finnishnot grpmax-eligible	0.00157%	63,880

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro148Ala
Coding: c.442C>G
MANE Select: NM_002511
dbSNP: rs148202124
Type: single nucleotide variant
Location: chr6:142078884 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 2 PDB

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-pro148ala (accessed [today's date]).

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