Is NFIX p.Arg116Trp (c.346C>T) pathogenic?

NFIX p.Arg116Trp (c.346C>T) is classified Pathogenic in NFIX (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-01). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with Malan overgrowth syndrome.

What condition is associated with NFIX p.Arg116Trp (c.346C>T)?

NFIX p.Arg116Trp (c.346C>T) is associated with Malan overgrowth syndrome (ClinVar).

How common is NFIX p.Arg116Trp (c.346C>T) in the general population?

NFIX p.Arg116Trp (c.346C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NFIX p.Arg116Trp (c.346C>T)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

NFIX p.Arg116Trp

c.346C>T · rs1555696603 · VCV559943

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Malan overgrowth syndrome

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 5% in NFIX
REVEL	0.752	pathogenic-leaning
SaProt	LLR -15.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.05	constrained · MANE · 128 bp · p 6.8e-13 · regional, not allelic
Overall
CADD	34.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NFIX
Protein: p.Arg116Trp
Coding: c.346C>T
MANE Select: NM_001365902
dbSNP: rs1555696603
Type: single nucleotide variant
Location: chr19:13025339 (GRCh38)
Gene constraint: LOEUF 0.092 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.94 · 3 PDB
Residue 116: a DNA-binding region; a UniProt-annotated variant site (in malns)

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

Similar variants

NFIX p.Arg116Gln Pathogenic/Likely pathogenic ★★ same residue
NFIX p.Arg116fs Pathogenic ★ same residue
NFIX p.Arg116Leu Likely pathogenic ★ same residue
NFIX p.Arg116Pro Pathogenic ★ same residue
NFIX p.Arg116= Likely benign ★ same residue
NFIX c.697+1G>A Pathogenic/Likely pathogenic ★★ same condition
NFIX c.818+1G>A Likely 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-arg116trp (accessed [today's date]).

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