Is MSX2 p.Ala35Pro (c.103G>C) pathogenic?

MSX2 p.Ala35Pro (c.103G>C) is classified Uncertain significance in MSX2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-11). AlphaMissense: likely benign (0.0758); Very rare (popmax 0.00383%, amr); Associated with Inborn genetic diseases.

What condition is associated with MSX2 p.Ala35Pro (c.103G>C)?

MSX2 p.Ala35Pro (c.103G>C) is associated with Inborn genetic diseases (ClinVar).

How common is MSX2 p.Ala35Pro (c.103G>C) in the general population?

MSX2 p.Ala35Pro (c.103G>C) is very rare (popmax 0.00383%, amr) (gnomAD).

What do computational predictors say about MSX2 p.Ala35Pro (c.103G>C)?

AlphaMissense predicts likely benign (score 0.0758) — an in-silico prediction, not a clinical call.

MSX2 p.Ala35Pro

c.103G>C · rs1210698589 · VCV1678262

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0758 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00383%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0758	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.16, phastCons 0.85
Regional constraint	o/e 1.14	unconstrained · MANE · 4,510 bp · p 0.06 · regional, not allelic
Overall
CADD	15.8	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 0.00383% Admixed American · 2/52,174 alleles

Filtering AF 0.000636% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000238%

Overall 0.000256% 4/1,561,804 alleles · very rare exomes 4/1,409,478 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00383%	26,087
European (non-Finnish)	0.000173%	576,974

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.Ala35Pro
Coding: c.103G>C
MANE Select: NM_002449
dbSNP: rs1210698589
Type: single nucleotide variant
Location: chr5:174724762 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 68.77
Residue 35: 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.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
MSX2 p.Arg162His Uncertain significance ★ ⚠ same condition
MSX2 p.Gly120Cys 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-ala35pro (accessed [today's date]).

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