Is NMBR p.Arg263Pro (c.788G>C) pathogenic?

NMBR p.Arg263Pro (c.788G>C) is classified Uncertain significance in NMBR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.9771); Very rare (popmax 0.00273%, afr).

How common is NMBR p.Arg263Pro (c.788G>C) in the general population?

NMBR p.Arg263Pro (c.788G>C) is very rare (popmax 0.00273%, afr) (gnomAD).

What do computational predictors say about NMBR p.Arg263Pro (c.788G>C)?

AlphaMissense predicts likely pathogenic (score 0.9771) — an in-silico prediction, not a clinical call.

NMBR p.Arg263Pro

c.788G>C · VCV3920444

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00273%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9771	likely pathogenic · top 4% in NMBR
REVEL	0.609	indeterminate
SaProt	LLR -15.92	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 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00021 · regional, not allelic
Overall
CADD	26.8	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 0.00273% African / African-American · 2/73,284 alleles

Filtering AF 0.000453% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.000569% 9/1,580,554 alleles · very rare exomes 7/1,428,328 · genomes 2/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00273%	36,642
European (non-Finnish)	0.0006%	166,550

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.Arg263Pro
Coding: c.788G>C
MANE Select: NM_002511
Type: single nucleotide variant
Location: chr6:142076033 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 2 PDB
Residue 263: an α-helix

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

Similar variants

NMBR p.Arg263His Uncertain significance ★ ⚠ same residue
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

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-arg263pro (accessed [today's date]).

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