Is NBAS p.Glu699Asp (c.2097G>C) pathogenic?

NBAS p.Glu699Asp (c.2097G>C) is classified Uncertain significance in NBAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: likely pathogenic (0.5722); Very rare (popmax 8.52e-05%, nfe).

How common is NBAS p.Glu699Asp (c.2097G>C) in the general population?

NBAS p.Glu699Asp (c.2097G>C) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about NBAS p.Glu699Asp (c.2097G>C)?

AlphaMissense predicts likely pathogenic (score 0.5722) — an in-silico prediction, not a clinical call.

NBAS p.Glu699Asp

c.2097G>C · VCV3907575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5722	likely pathogenic
REVEL	0.26	benign-leaning
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.77	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.80	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 394 kb · p 0.09 · regional, not allelic
Overall
CADD	29.9	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 8.52e-05% European (non-Finnish) · 1/1,173,598 alleles

Overall 6.22e-05% 1/1,606,776 alleles · very rare exomes 1/1,454,564 · genomes 0/152,212 · joint denominator

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: NBAS
Protein: p.Glu699Asp
Coding: c.2097G>C
MANE Select: NM_015909
Type: single nucleotide variant
Location: chr2:15467329 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 699: a UniProt-annotated variant site (in ilfs2; uncertain significance); a UniProt-annotated variant site (found in a patient with a multisystem disease involving liver, eye, immune system, connective tissue and bone; uncertain significance); a UniProt-annotated variant site (found in a patient with a multisystem disease involving liver, eye, immune system, connective tissue and bone; uncertain significance; reduced protein expression levels in fibroblasts); the 'interaction with use1' region

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

Similar variants

NBAS p.Glu699= Uncertain significance ★ same residue
NBAS c.1726-2A>G Likely pathogenic ★★ same type
NBAS c.173-2A>G Likely pathogenic ★★ same type
NBAS c.209+2T>G Pathogenic/Likely pathogenic ★★ same type
NBAS c.2423+404G>C Likely pathogenic ★★ same type
NBAS c.335+1G>C Pathogenic/Likely pathogenic ★★ same type
NBAS c.4461+2T>C Likely pathogenic ★★ same type
NBAS c.4583-2A>G Likely pathogenic ★★ 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/nbas-p-glu699asp (accessed [today's date]).

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