Is NFIX p.Pro313Ser (c.937C>T) pathogenic?

NFIX p.Pro313Ser (c.937C>T) is classified Likely benign in NFIX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: likely benign (0.1282); Absent from gnomAD v4.1; Associated with Marshall-Smith syndrome.

What condition is associated with NFIX p.Pro313Ser (c.937C>T)?

NFIX p.Pro313Ser (c.937C>T) is associated with Marshall-Smith syndrome, Malan overgrowth syndrome (ClinVar).

How common is NFIX p.Pro313Ser (c.937C>T) in the general population?

NFIX p.Pro313Ser (c.937C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NFIX p.Pro313Ser (c.937C>T)?

AlphaMissense predicts likely benign (score 0.1282) — an in-silico prediction, not a clinical call.

NFIX p.Pro313Ser

c.937C>T · VCV3756720

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1282 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Marshall-Smith syndrome

Computational evidence

Protein change
AlphaMissense	0.1282	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 56 kb · p 9.3e-13 · regional, not allelic
Overall
CADD	26.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NFIX
Protein: p.Pro313Ser
Coding: c.937C>T
MANE Select: NM_001365902
Type: single nucleotide variant
Location: chr19:13075653 (GRCh38)
Gene constraint: LOEUF 0.092 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.94 · 3 PDB
Residue 313: 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-pro313ser (accessed [today's date]).

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