Is NFIX p.Asp458= (c.1374C>T) pathogenic?

NFIX p.Asp458= (c.1374C>T) is classified Likely benign in NFIX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-09). Very rare (popmax 0.00476%, sas); Associated with Marshall-Smith syndrome.

What condition is associated with NFIX p.Asp458= (c.1374C>T)?

NFIX p.Asp458= (c.1374C>T) is associated with Marshall-Smith syndrome, Malan overgrowth syndrome (ClinVar).

How common is NFIX p.Asp458= (c.1374C>T) in the general population?

NFIX p.Asp458= (c.1374C>T) is very rare (popmax 0.00476%, sas) (gnomAD).

NFIX p.Asp458=

c.1374C>T · VCV4788393

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00476%, sas)

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 1.8	GERP -0.28, phastCons 1
Overall
CADD	14.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00476% South Asian · 4/84,064 alleles

Filtering AF 0.00161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000949%

Overall 0.000976% 15/1,536,532 alleles · very rare exomes 13/1,384,278 · genomes 2/152,254 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00476%	21,016
Admixed American	0.00392%	25,495
Remaining individualsnot grpmax-eligible	0.00333%	30,056
African / African-American	0.00137%	73,064
European (non-Finnish)	0.000523%	191,169

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.Asp458=
Coding: c.1374C>T
MANE Select: NM_001365902
Type: single nucleotide variant
Location: chr19:13088108 (GRCh38)
Gene constraint: LOEUF 0.092 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.94 · 3 PDB
Residue 458: the 'disordered' region

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-asp458 (accessed [today's date]).

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