Is NFIX p.Ser219Ala (c.655T>G) pathogenic?

NFIX p.Ser219Ala (c.655T>G) is classified Uncertain significance in NFIX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-01). AlphaMissense: likely benign (0.1691); Very rare (popmax 0.00133%, afr).

How common is NFIX p.Ser219Ala (c.655T>G) in the general population?

NFIX p.Ser219Ala (c.655T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about NFIX p.Ser219Ala (c.655T>G)?

AlphaMissense predicts likely benign (score 0.1691) — an in-silico prediction, not a clinical call.

NFIX p.Ser219Ala

c.655T>G · rs1300698946 · VCV2649364

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1691	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -11.30	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 56 kb · p 9.3e-13 · regional, not allelic
Overall
CADD	28.3	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

Grpmax group 0.00133% African / African-American · 1/74,930 alleles

Overall 6.2e-05% 1/1,613,900 alleles · very rare exomes 0/1,461,698 · genomes 1/152,202 · joint denominator

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.Ser219Ala
Coding: c.655T>G
MANE Select: NM_001365902
dbSNP: rs1300698946
Type: single nucleotide variant
Location: chr19:13073454 (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

Similar variants

NFIX c.559+1G>A Pathogenic ★★ same type
NFIX c.697+1G>A Pathogenic/Likely pathogenic ★★ same type
NFIX c.818+1G>A Likely pathogenic ★★ same type
NFIX c.955+1G>A Pathogenic ★★ same type
NFIX c.955+1G>T Pathogenic ★★ same type
NFIX p.Arg115Gln Pathogenic/Likely pathogenic ★★ same type
NFIX p.Arg116Gln Pathogenic/Likely pathogenic ★★ same type
NFIX p.Arg116Trp Pathogenic ★★ same type

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-ser219ala (accessed [today's date]).

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