Is NBN p.Val114Phe (c.340G>T) pathogenic?

NBN p.Val114Phe (c.340G>T) is classified Conflicting classifications of pathogenicity in NBN (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-09-19). AlphaMissense: likely benign (0.2887); Ultra-rare (popmax 0.0165%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Val114Phe (c.340G>T)?

NBN p.Val114Phe (c.340G>T) is associated with hereditary neoplastic syndrome, acute lymphoblastic leukemia, Nijmegen breakage syndrome (ClinVar).

How common is NBN p.Val114Phe (c.340G>T) in the general population?

NBN p.Val114Phe (c.340G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about NBN p.Val114Phe (c.340G>T)?

AlphaMissense predicts likely benign (score 0.2887) — an in-silico prediction, not a clinical call.

NBN p.Val114Phe

c.340G>T · rs771034958 · VCV219644

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2887 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2887	likely benign
REVEL	0.465	indeterminate
SaProt	LLR -11.27	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.46	acceptor loss · deltas
Pangolin	Δ0.54	gain · loss 0.51 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Overall
CADD	23.5	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 0.0165% Middle Eastern · 1/6,054 alleles

Overall 0.000137% 2/1,460,496 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
European (non-Finnish)	8.48e-05%	1,179,270

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.Val114Phe
Coding: c.340G>T
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs771034958
Type: single nucleotide variant
Location: chr8:89980874 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB
Residue 114: the 'disordered' region

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: acute lymphoblastic leukemia Nijmegen breakage syndrome aplastic anemia

Similar variants

NBN p.Val114Ile Uncertain significance ★★ ⚠ same residue
NBN p.Val114= Uncertain significance ★ same residue
NBN p.Val114Gly Uncertain significance ★ ⚠ same residue
NBN p.Val114Leu Uncertain significance ★ ⚠ 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-val114phe (accessed [today's date]).

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