Is NFIX p.His395= (c.1185C>T) pathogenic?

NFIX p.His395= (c.1185C>T) is classified Likely benign in NFIX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-05). Very rare (popmax 0.00223%, eas); Associated with Marshall-Smith syndrome.

What condition is associated with NFIX p.His395= (c.1185C>T)?

NFIX p.His395= (c.1185C>T) is associated with Marshall-Smith syndrome, Malan overgrowth syndrome (ClinVar).

How common is NFIX p.His395= (c.1185C>T) in the general population?

NFIX p.His395= (c.1185C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

NFIX p.His395=

c.1185C>T · rs752829674 · VCV1983521

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 -5.2	GERP -1.4
Overall
CADD	8.187	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00149% 24/1,614,042 alleles · very rare exomes 24/1,461,682 · genomes 0/152,360 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
European (non-Finnish)	0.00178%	56,186
Finnishnot grpmax-eligible	0.00156%	64,014
South Asian	0.0011%	91,086

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.His395=
Coding: c.1185C>T
MANE Select: NM_001365902
dbSNP: rs752829674
Type: single nucleotide variant
Location: chr19:13081786 (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 p.His395_Gly396insHis Likely benign ★★ same residue
NFIX p.His395fs Likely pathogenic ★ 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

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-his395 (accessed [today's date]).

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