Is NBAS p.Ile2008Val (c.6022A>G) pathogenic?

NBAS p.Ile2008Val (c.6022A>G) is classified Conflicting classifications of pathogenicity in NBAS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-22). AlphaMissense: likely benign (0.0862); Ultra-rare (popmax 0.036%, afr); Associated with short stature-optic atrophy-Pelger-Huët anomaly syndrome.

How common is NBAS p.Ile2008Val (c.6022A>G) in the general population?

NBAS p.Ile2008Val (c.6022A>G) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about NBAS p.Ile2008Val (c.6022A>G)?

AlphaMissense predicts likely benign (score 0.0862) — an in-silico prediction, not a clinical call.

NBAS p.Ile2008Val

Q: What condition is associated with NBAS p.Ile2008Val (c.6022A>G)?

NBAS p.Ile2008Val (c.6022A>G) is associated with short stature-optic atrophy-Pelger-Huët anomaly syndrome, infantile liver failure syndrome 2 (ClinVar).

c.6022A>G · rs370669818 · VCV1439266

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0862 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

short stature-optic atrophy-Pelger-Huët anomaly syndrome

Computational evidence

Protein change
AlphaMissense	0.0862	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -6.03	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 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 394 kb · p 0.09 · regional, not allelic
Overall
CADD	22.7	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 0.036% African / African-American · 27/74,928 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00297% 48/1,614,062 alleles · ultra-rare exomes 30/1,461,856 · genomes 18/152,206 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,775
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Admixed American	0.00333%	30,003
European (non-Finnish)	0.00127%	78,668

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.Ile2008Val
Coding: c.6022A>G
MANE Select: NM_015909
dbSNP: rs370669818
Type: single nucleotide variant
Location: chr2:15234669 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 2008: 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); 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 collagen secretion; diffuse collagen bundles; reduced protein expression in fibroblasts); the 'interaction with zw10 and rint1' region

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

Disease context

short stature-optic atrophy-Pelger-Huët anomaly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: infantile liver failure syndrome 2

Similar variants

NBAS p.Ile2008= Likely benign ★ same residue
NBAS c.173-2A>G Likely pathogenic ★★ same condition
NBAS c.2423+404G>C Likely pathogenic ★★ same condition
NBAS c.335+1G>C Pathogenic/Likely pathogenic ★★ same condition
NBAS c.4583-2A>G Likely pathogenic ★★ same condition
NBAS c.513+2T>C Pathogenic/Likely pathogenic ★★ same condition
NBAS c.886-5T>A Likely pathogenic ★★ same condition
NBAS p.Arg1004Ter 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/nbas-p-ile2008val (accessed [today's date]).

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