Is NMBR p.Arg263His (c.788G>A) pathogenic?

NMBR p.Arg263His (c.788G>A) is classified Uncertain significance in NMBR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely benign (0.2198); Very rare (popmax 0.00273%, afr).

How common is NMBR p.Arg263His (c.788G>A) in the general population?

NMBR p.Arg263His (c.788G>A) is very rare (popmax 0.00273%, afr) (gnomAD).

What do computational predictors say about NMBR p.Arg263His (c.788G>A)?

AlphaMissense predicts likely benign (score 0.2198) — an in-silico prediction, not a clinical call.

NMBR p.Arg263His

c.788G>A · VCV3880065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2198 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00273%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2198	likely benign
REVEL	0.34	indeterminate
SaProt	LLR -9.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; 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	25.9	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 0.00273% African / African-American · 2/73,162 alleles

Filtering AF 0.00159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.0019% 30/1,580,436 alleles · very rare exomes 29/1,428,328 · genomes 1/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00273%	36,581
European (non-Finnish)	0.00232%	43,180
South Asian	0.00117%	85,364

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.Arg263His
Coding: c.788G>A
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.Arg263Pro 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-arg263his (accessed [today's date]).

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