Is NFIX p.Ile16= (c.48C>T) pathogenic?

NFIX p.Ile16= (c.48C>T) is classified Likely benign in NFIX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). Ultra-rare (popmax 0.0291%, eas); Associated with Marshall-Smith syndrome.

What condition is associated with NFIX p.Ile16= (c.48C>T)?

NFIX p.Ile16= (c.48C>T) is associated with Marshall-Smith syndrome, Malan overgrowth syndrome (ClinVar).

How common is NFIX p.Ile16= (c.48C>T) in the general population?

NFIX p.Ile16= (c.48C>T) is ultra-rare (popmax 0.0291%, eas) (gnomAD).

NFIX p.Ile16=

c.48C>T · rs559433211 · VCV758814

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0291%, eas)

Conditions

Marshall-Smith syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.7	GERP -1.7, phastCons 1
Overall
CADD	13.47	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0291% East Asian · 13/44,724 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00118% 19/1,611,080 alleles · ultra-rare exomes 17/1,458,768 · genomes 2/152,312 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0291%	3,440
South Asian	0.00551%	18,150
European (non-Finnish)	8.49e-05%	1,178,541

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: NFIX
Protein: p.Ile16=
Coding: c.48C>T
MANE Select: NM_001365902
dbSNP: rs559433211
Type: single nucleotide variant
Location: chr19:13025041 (GRCh38)
Gene constraint: LOEUF 0.092 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.94 · 3 PDB
Residue 16: a DNA-binding region; an α-helix

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

Disease context

Marshall-Smith syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Malan overgrowth syndrome

Similar variants

NFIX p.Ile16fs Pathogenic same residue
NFIX c.697+1G>A Pathogenic/Likely pathogenic ★★ same condition
NFIX c.818+1G>A Likely pathogenic ★★ same condition
NFIX c.955+1G>A Pathogenic ★★ same condition
NFIX c.955+1G>T Pathogenic ★★ same condition
NFIX p.Arg116Gln Pathogenic/Likely pathogenic ★★ same condition
NFIX p.Arg116Trp Pathogenic ★★ same condition
NFIX p.Arg128Gln 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/nfix-p-ile16 (accessed [today's date]).

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