Is NFIX p.Arg84= (c.252G>T) pathogenic?

NFIX p.Arg84= (c.252G>T) is classified Likely benign in NFIX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-07). Ultra-rare (popmax 0.0111%, nfe); Associated with Malan overgrowth syndrome.

What condition is associated with NFIX p.Arg84= (c.252G>T)?

NFIX p.Arg84= (c.252G>T) is associated with Malan overgrowth syndrome, Marshall-Smith syndrome (ClinVar).

How common is NFIX p.Arg84= (c.252G>T) in the general population?

NFIX p.Arg84= (c.252G>T) is ultra-rare (popmax 0.0111%, nfe) (gnomAD).

NFIX p.Arg84=

c.252G>T · rs769513682 · VCV771267

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, nfe)

Conditions

Malan overgrowth 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 5.9	GERP 1.6, phastCons 1
Overall
CADD	14.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% European (non-Finnish) · 131/1,179,998 alleles

Filtering AF 0.00952% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00896%

Overall 0.00843% 136/1,614,042 alleles · ultra-rare exomes 129/1,461,808 · genomes 7/152,234 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0111%	9,008
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Finnishnot grpmax-eligible	0.00156%	64,018

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.Arg84=
Coding: c.252G>T
MANE Select: NM_001365902
dbSNP: rs769513682
Type: single nucleotide variant
Location: chr19:13025245 (GRCh38)
Gene constraint: LOEUF 0.092 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.94 · 3 PDB
Residue 84: a DNA-binding region

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

Disease context

Malan overgrowth syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Marshall-Smith syndrome

Similar variants

NFIX p.Arg84fs Likely 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-arg84 (accessed [today's date]).

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