Is MSX2 p.Ser43Phe (c.128C>T) pathogenic?

MSX2 p.Ser43Phe (c.128C>T) is classified Uncertain significance in MSX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.3197); Very rare (popmax 0.000261%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MSX2 p.Ser43Phe (c.128C>T)?

MSX2 p.Ser43Phe (c.128C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MSX2 p.Ser43Phe (c.128C>T) in the general population?

MSX2 p.Ser43Phe (c.128C>T) is very rare (popmax 0.000261%, nfe) (gnomAD).

What do computational predictors say about MSX2 p.Ser43Phe (c.128C>T)?

AlphaMissense predicts likely benign (score 0.3197) — an in-silico prediction, not a clinical call.

MSX2 p.Ser43Phe

c.128C>T · VCV4111442

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000261%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3197	likely benign
REVEL	0.546	indeterminate
SaProt	LLR -3.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 4,510 bp · p 0.06 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000261% European (non-Finnish) · 3/1,149,902 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000214% 3/1,402,644 alleles · very rare

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: MSX2
Protein: p.Ser43Phe
Coding: c.128C>T
MANE Select: NM_002449
Type: single nucleotide variant
Location: chr5:174724787 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 68.77
Residue 43: the 'disordered' region

Full MSX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MSX2 p.Ser43Pro Uncertain significance ★ ⚠ same residue
MSX2 p.Ala35Pro Uncertain significance ★★ ⚠ same condition
MSX2 p.Arg159His Uncertain significance ★★ ⚠ same condition
MSX2 p.Gly25Arg Uncertain significance ★★ ⚠ same condition
MSX2 p.His90Gln Uncertain significance ★★ ⚠ same condition
MSX2 p.Met263Ile Uncertain significance ★★ ⚠ same condition
MSX2 p.Pro225Arg Uncertain significance ★★ ⚠ same condition
MSX2 p.Ser106Pro Uncertain significance ★★ ⚠ 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/msx2-p-ser43phe (accessed [today's date]).

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