Is NUCB2 p.Pro26Arg (c.77C>G) pathogenic?

NUCB2 p.Pro26Arg (c.77C>G) is classified Uncertain significance in NUCB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely pathogenic (0.5906); Ultra-rare (popmax 0.0247%, nfe).

How common is NUCB2 p.Pro26Arg (c.77C>G) in the general population?

NUCB2 p.Pro26Arg (c.77C>G) is ultra-rare (popmax 0.0247%, nfe) (gnomAD).

What do computational predictors say about NUCB2 p.Pro26Arg (c.77C>G)?

AlphaMissense predicts likely pathogenic (score 0.5906) — an in-silico prediction, not a clinical call.

NUCB2 p.Pro26Arg

c.77C>G · VCV3301352

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5906 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0247%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5906	likely pathogenic
REVEL	0.389	indeterminate
SaProt	LLR -8.65	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 36 kb · p 0.12 · regional, not allelic
Overall
CADD	24.2	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 0.0247% European (non-Finnish) · 291/1,179,702 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.0193% 312/1,613,308 alleles · ultra-rare exomes 296/1,461,222 · genomes 16/152,086 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0247%	4,054
Remaining individualsnot grpmax-eligible	0.0224%	4,461
Admixed American	0.00668%	14,976
Finnishnot grpmax-eligible	0.00313%	31,995
African / African-American	0.00134%	74,870

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: NUCB2
Protein: p.Pro26Arg
Coding: c.77C>G
MANE Select: NM_005013
Type: single nucleotide variant
Location: chr11:17295400 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 84.43

Full NUCB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NUCB2 p.Ala161Thr Uncertain significance ★ ⚠ same type
NUCB2 p.Ala161Val Uncertain significance ★ ⚠ same type
NUCB2 p.Ala162Val Uncertain significance ★ ⚠ same type
NUCB2 p.Ala21Val Uncertain significance ★ ⚠ same type
NUCB2 p.Ala43Glu Uncertain significance ★ ⚠ same type
NUCB2 p.Ala43Val Uncertain significance ★ ⚠ same type
NUCB2 p.Arg108Lys Uncertain significance ★ ⚠ same type
NUCB2 p.Asn352Ser 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/nucb2-p-pro26arg (accessed [today's date]).

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