Is NBN p.Ser615Pro (c.1843T>C) pathogenic?

NBN p.Ser615Pro (c.1843T>C) is classified Conflicting classifications of pathogenicity in NBN (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2025-09-29). AlphaMissense: likely benign (0.0641); Very rare (popmax 0.00886%, nfe); Associated with aplastic anemia.

What condition is associated with NBN p.Ser615Pro (c.1843T>C)?

NBN p.Ser615Pro (c.1843T>C) is associated with aplastic anemia, acute lymphoblastic leukemia, Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Ser615Pro (c.1843T>C) in the general population?

NBN p.Ser615Pro (c.1843T>C) is very rare (popmax 0.00886%, nfe) (gnomAD).

What do computational predictors say about NBN p.Ser615Pro (c.1843T>C)?

AlphaMissense predicts likely benign (score 0.0641) — an in-silico prediction, not a clinical call.

NBN p.Ser615Pro

c.1843T>C · rs746632073 · VCV411782

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00886%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aplastic anemia

Computational evidence

Protein change
AlphaMissense	0.0641	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -7.32	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 -0.57	GERP 0.53
Overall
CADD	10.39	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 0.00886% European (non-Finnish) · 103/1,162,962 alleles

Filtering AF 0.00743% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00694%

Overall 0.00677% 108/1,594,234 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00886%	11,291
African / African-American	0.00403%	24,815
Remaining individualsnot grpmax-eligible	0.00323%	30,923

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.Ser615Pro
Coding: c.1843T>C
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs746632073
Type: single nucleotide variant
Location: chr8:89953246 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB

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

Disease context

aplastic anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acute lymphoblastic leukemia Nijmegen breakage syndrome hereditary neoplastic syndrome

Similar variants

NBN p.Ser615Cys Uncertain significance ★★ ⚠ same residue
NBN p.Ser615Phe Uncertain significance ★★ ⚠ same residue
NBN p.Ser615= Conflicting classifications of pathogenicity ★ 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
NBN c.172-1G>T 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-ser615pro (accessed [today's date]).

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