Is NBAS p.Leu741= (c.2223G>A) pathogenic?

NBAS p.Leu741= (c.2223G>A) is classified Benign in NBAS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 67.9%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with short stature-optic atrophy-Pelger-Huët anomaly syndrome.

NBAS p.Leu741=

Q: What condition is associated with NBAS p.Leu741= (c.2223G>A)?

NBAS p.Leu741= (c.2223G>A) is associated with short stature-optic atrophy-Pelger-Huët anomaly syndrome, infantile liver failure syndrome 2 (ClinVar).

Q: How common is NBAS p.Leu741= (c.2223G>A) in the general population?

NBAS p.Leu741= (c.2223G>A) is common (popmax 67.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2223G>A · rs7590340 · VCV1169870

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 67.9%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

short stature-optic atrophy-Pelger-Huët anomaly syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.94	GERP -4, phastCons 0.004
Overall
CADD	1.176	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 67.9% European (non-Finnish) · 799,210/1,177,712 alleles

Filtering AF 67.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 67.7%

Overall 65% 1,046,804/1,611,108 alleles · common exomes 952,013/1,459,330 · genomes 94,791/151,778 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	74%	1
Ashkenazi Jewishnot grpmax-eligible	72.3%	1
European (non-Finnish)grpmax	67.9%	1
Middle Eastern	67%	1
Remaining individualsnot grpmax-eligible	63.7%	2
Admixed American	58.7%	2
South Asian	58.6%	2
African / African-American	58.3%	2
Finnishnot grpmax-eligible	58.1%	2
East Asian	27.7%	4

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu741=
Coding: c.2223G>A
MANE Select: NM_015909
dbSNP: rs7590340
Type: single nucleotide variant
Location: chr2:15461317 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 741: 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

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.Leu741Val Uncertain significance ★★ ⚠ same residue
NBAS p.Leu741Arg Uncertain significance ★ ⚠ 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

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-leu741 (accessed [today's date]).

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