Is NFIX p.His22= (c.66C>T) pathogenic?

NFIX p.His22= (c.66C>T) is classified Likely benign in NFIX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). Very rare (popmax 0.0022%, sas); Associated with Malan overgrowth syndrome.

What condition is associated with NFIX p.His22= (c.66C>T)?

NFIX p.His22= (c.66C>T) is associated with Malan overgrowth syndrome, Marshall-Smith syndrome (ClinVar).

How common is NFIX p.His22= (c.66C>T) in the general population?

NFIX p.His22= (c.66C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

NFIX p.His22=

c.66C>T · rs770391394 · VCV2933692

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Malan overgrowth 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 1.7, phastCons 1
Overall
CADD	14.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,018 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.00062% 10/1,613,736 alleles · very rare exomes 10/1,461,440 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,243
South Asiangrpmax	0.0022%	45,509
European (non-Finnish)	0.000509%	196,632

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His22=
Coding: c.66C>T
MANE Select: NM_001365902
dbSNP: rs770391394
Type: single nucleotide variant
Location: chr19:13025059 (GRCh38)
Gene constraint: LOEUF 0.092 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.94 · 3 PDB
Residue 22: 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

Also linked: Marshall-Smith syndrome

Similar variants

NFIX p.His22fs Pathogenic ★ same residue
NFIX p.His22Asp Uncertain significance ★ ⚠ 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-his22 (accessed [today's date]).

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