Is NFIX p.Arg115Trp (c.343C>T) pathogenic?

NFIX p.Arg115Trp (c.343C>T) is classified Likely pathogenic in NFIX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with Malan overgrowth syndrome.

What condition is associated with NFIX p.Arg115Trp (c.343C>T)?

NFIX p.Arg115Trp (c.343C>T) is associated with Malan overgrowth syndrome (ClinVar).

How common is NFIX p.Arg115Trp (c.343C>T) in the general population?

NFIX p.Arg115Trp (c.343C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NFIX p.Arg115Trp (c.343C>T)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

NFIX p.Arg115Trp

c.343C>T · VCV3775206

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · 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	0.9994	likely pathogenic ✓ concordant with ClinVar · top 5% in NFIX
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -13.09	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 2.8, 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.Arg115Trp
Coding: c.343C>T
MANE Select: NM_001365902
Type: single nucleotide variant
Location: chr19:13025336 (GRCh38)
Gene constraint: LOEUF 0.092 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.94 · 3 PDB
Residue 115: a DNA-binding region; an α-helix

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.Arg115Gln Pathogenic/Likely pathogenic ★★ same residue
NFIX p.Arg115Leu Likely pathogenic ★ same residue
NFIX c.697+1G>A Pathogenic/Likely pathogenic ★★ same condition
NFIX c.818+1G>A Likely 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-arg115trp (accessed [today's date]).

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