Is MSN p.Ile227Phe (c.679A>T) pathogenic?

MSN p.Ile227Phe (c.679A>T) is classified Uncertain significance in MSN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-02). AlphaMissense: likely pathogenic (0.9958); Absent from gnomAD v4.1.

How common is MSN p.Ile227Phe (c.679A>T) in the general population?

MSN p.Ile227Phe (c.679A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSN p.Ile227Phe (c.679A>T)?

AlphaMissense predicts likely pathogenic (score 0.9958) — an in-silico prediction, not a clinical call.

MSN p.Ile227Phe

c.679A>T · rs2523006339 · VCV1712669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9958 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9958	likely pathogenic
REVEL	0.893	moderately pathogenic-leaning
SaProt	LLR -14.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.09	constrained · MANE · 97 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: MSN
Protein: p.Ile227Phe
Coding: c.679A>T
MANE Select: NM_002444
dbSNP: rs2523006339
Type: single nucleotide variant
Location: chrX:65731965 (GRCh38)
Structure: AlphaFold pLDDT 86.77 · 10 PDB
Residue 227: the ferm domain; a β-strand

Full MSN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MSN p.Arg171Trp Pathogenic ★★ same type
MSN p.Ala122Thr Uncertain significance ★★ ⚠ same type
MSN p.Arg273Trp Uncertain significance ★★ ⚠ same type
MSN p.Arg293Cys Uncertain significance ★★ ⚠ same type
MSN p.Arg294Cys Uncertain significance ★★ ⚠ same type
MSN p.Arg295His Uncertain significance ★★ ⚠ same type
MSN p.Arg393His Uncertain significance ★★ ⚠ same type
MSN p.Glu346Asp Uncertain significance ★★ ⚠ 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/msn-p-ile227phe (accessed [today's date]).

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