Is NBN p.Pro593Ala (c.1777C>G) pathogenic?

NBN p.Pro593Ala (c.1777C>G) is classified Conflicting classifications of pathogenicity in NBN (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-03-03). AlphaMissense: likely benign (0.1049); Rare (popmax 0.216%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Pro593Ala (c.1777C>G)?

NBN p.Pro593Ala (c.1777C>G) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Pro593Ala (c.1777C>G) in the general population?

NBN p.Pro593Ala (c.1777C>G) is rare (popmax 0.216%, afr) (gnomAD).

What do computational predictors say about NBN p.Pro593Ala (c.1777C>G)?

AlphaMissense predicts likely benign (score 0.1049) — an in-silico prediction, not a clinical call.

NBN p.Pro593Ala

c.1777C>G · rs146989944 · VCV127862

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.1049 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.216%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1049	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -6.31	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 2.5	GERP -0.94, phastCons 1
Overall
CADD	17.21	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 0.216% African / African-American · 162/74,956 alleles

Filtering AF 0.189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.179%

Overall 0.0105% 169/1,613,202 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.216%	463
Admixed American	0.00667%	14,995
Remaining individualsnot grpmax-eligible	0.0048%	20,831

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: NBN
Protein: p.Pro593Ala
Coding: c.1777C>G
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs146989944
Type: single nucleotide variant
Location: chr8:89953312 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Nijmegen breakage syndrome

Similar variants

NBN p.Pro593= Likely benign ★★ same residue
NBN p.Pro593Ser Uncertain significance ★ ⚠ same residue
NBN p.Pro593Thr Uncertain significance ★ ⚠ same residue
NBN p.Pro593_Arg594insAlaGlyArgGlyGlySerArgLeuTer Pathogenic ★ same residue
NBN c.1124+1G>C Likely pathogenic ★★ same condition
NBN c.1124+2T>G Likely pathogenic ★★ same condition
NBN c.1397+2T>A Likely pathogenic ★★ same condition
NBN c.171+1G>A Likely pathogenic ★★ same condition

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/nbn-p-pro593ala (accessed [today's date]).

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