Is NBAS p.Ile243Val (c.727A>G) pathogenic?

NBAS p.Ile243Val (c.727A>G) is classified Benign in NBAS (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0579); Common (popmax 67.6%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with short stature-optic atrophy-Pelger-Huët anomaly syndrome.

What do computational predictors say about NBAS p.Ile243Val (c.727A>G)?

AlphaMissense predicts likely benign (score 0.0579) — an in-silico prediction, not a clinical call.

NBAS p.Ile243Val

Q: What condition is associated with NBAS p.Ile243Val (c.727A>G)?

NBAS p.Ile243Val (c.727A>G) is associated with short stature-optic atrophy-Pelger-Huët anomaly syndrome, infantile liver failure syndrome 2 (ClinVar).

Q: How common is NBAS p.Ile243Val (c.727A>G) in the general population?

NBAS p.Ile243Val (c.727A>G) is common (popmax 67.6%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.727A>G · rs13029846 · VCV1169874

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0579 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 67.6%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

short stature-optic atrophy-Pelger-Huët anomaly syndrome

Computational evidence

Protein change
AlphaMissense	0.0579	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -5.90	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 -4.9	GERP -3.7
Regional constraint	o/e 1.03	unconstrained · MANE · 394 kb · p 0.09 · regional, not allelic
Overall
CADD	0.568	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 67.6% European (non-Finnish) · 794,621/1,175,296 alleles

Filtering AF 67.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 67.4%

Overall 62.3% 1,002,859/1,608,724 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	74.3%	1
Ashkenazi Jewishnot grpmax-eligible	70.5%	1
European (non-Finnish)grpmax	67.6%	1
Middle Eastern	62.7%	2
Remaining individualsnot grpmax-eligible	59.7%	2
Finnishnot grpmax-eligible	58%	2
Admixed American	54.4%	2
South Asian	49.7%	2
African / African-American	27.8%	4
East Asian	22.3%	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.Ile243Val
Coding: c.727A>G
MANE Select: NM_015909
dbSNP: rs13029846
Type: single nucleotide variant
Location: chr2:15534562 (GRCh38)
Gene constraint: LOEUF 0.761 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.42
Residue 243: a UniProt-annotated variant site (in ilfs2; uncertain significance); a UniProt-annotated variant site (in); 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 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
NBAS p.Arg1236Ter Pathogenic/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-ile243val (accessed [today's date]).

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