Is NFIX p.Pro342= (c.1026G>A) pathogenic?

NFIX p.Pro342= (c.1026G>A) is classified Benign/Likely benign in NFIX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-01). Ultra-rare (popmax 0.0999%, amr); Associated with Marshall-Smith syndrome.

What condition is associated with NFIX p.Pro342= (c.1026G>A)?

NFIX p.Pro342= (c.1026G>A) is associated with Marshall-Smith syndrome, Malan overgrowth syndrome (ClinVar).

How common is NFIX p.Pro342= (c.1026G>A) in the general population?

NFIX p.Pro342= (c.1026G>A) is ultra-rare (popmax 0.0999%, amr) (gnomAD).

NFIX p.Pro342=

c.1026G>A · rs774838479 · VCV1613310

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0999%, amr)

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 -3.4, phastCons 1
Overall
CADD	8.891	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0999% Admixed American · 58/58,064 alleles

Filtering AF 0.0793% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0719%

Overall 0.00738% 118/1,599,182 alleles · ultra-rare exomes 101/1,447,052 · genomes 17/152,130 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0999%	1,001
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.00484%	20,643
East Asian	0.00452%	22,126
European (non-Finnish)	0.00452%	22,138
African / African-American	0.00134%	74,588

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.Pro342=
Coding: c.1026G>A
MANE Select: NM_001365902
dbSNP: rs774838479
Type: single nucleotide variant
Location: chr19:13078683 (GRCh38)
Gene constraint: LOEUF 0.092 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.94 · 3 PDB

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 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
NFIX p.Arg128Trp 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-pro342 (accessed [today's date]).

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