Is NFIX p.Ser412= (c.1236G>A) pathogenic?

NFIX p.Ser412= (c.1236G>A) is classified Benign in NFIX (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-25). Rare (popmax 0.993%, sas); Associated with Marshall-Smith syndrome.

What condition is associated with NFIX p.Ser412= (c.1236G>A)?

NFIX p.Ser412= (c.1236G>A) is associated with Marshall-Smith syndrome, Malan overgrowth syndrome (ClinVar).

How common is NFIX p.Ser412= (c.1236G>A) in the general population?

NFIX p.Ser412= (c.1236G>A) is rare (popmax 0.993%, sas) (gnomAD).

NFIX p.Ser412=

c.1236G>A · rs367955217 · VCV767492

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.993%, 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 -1.6	GERP -4.4
Overall
CADD	7.837	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.993% South Asian · 904/91,076 alleles

Filtering AF 0.939% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.917%

Overall 0.0637% 1,028/1,613,910 alleles · rare exomes 970/1,461,580 · genomes 58/152,330 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.993%	101
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.08%	1,250
Admixed American	0.0633%	1,579
African / African-American	0.0306%	3,264
European (non-Finnish)	0.000678%	147,486

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.Ser412=
Coding: c.1236G>A
MANE Select: NM_001365902
dbSNP: rs367955217
Type: single nucleotide variant
Location: chr19:13081837 (GRCh38)
Gene constraint: LOEUF 0.092 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.94 · 3 PDB
Residue 412: 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 p.Ser412Leu Conflicting classifications of pathogenicity ★ ⚠ 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-ser412 (accessed [today's date]).

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