Is SMCHD1 p.Pro140= (c.420T>G) pathogenic?

SMCHD1 p.Pro140= (c.420T>G) is classified Likely benign in SMCHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-30). Very rare (popmax 8.65e-05%, nfe); Associated with facioscapulohumeral muscular dystrophy 2.

What condition is associated with SMCHD1 p.Pro140= (c.420T>G)?

SMCHD1 p.Pro140= (c.420T>G) is associated with facioscapulohumeral muscular dystrophy 2 (ClinVar).

How common is SMCHD1 p.Pro140= (c.420T>G) in the general population?

SMCHD1 p.Pro140= (c.420T>G) is very rare (popmax 8.65e-05%, nfe) (gnomAD).

How is Facioscapulohumeral dystrophy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

SMCHD1 p.Pro140=

c.420T>G · rs2143806315 · VCV1626979

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.65e-05%, nfe)

Conditions

facioscapulohumeral muscular dystrophy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP -0.18, phastCons 1
Overall
CADD	11.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.65e-05% European (non-Finnish) · 1/1,155,642 alleles

Overall 6.36e-05% 1/1,571,564 alleles · very rare exomes 1/1,419,244 · genomes 0/152,320 · 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: SMCHD1
Protein: p.Pro140=
Coding: c.420T>G
MANE Select: NM_015295
dbSNP: rs2143806315
Type: single nucleotide variant
Location: chr18:2667027 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.17 · 1 PDB
Residue 140: a UniProt-annotated variant site (in fshd2); the 'atpase activity domain' region

Full SMCHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

facioscapulohumeral muscular dystrophy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Facioscapulohumeral dystrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

SMCHD1 c.1040+1G>A Pathogenic ★★ same condition
SMCHD1 p.Arg1423Ter Pathogenic/Likely pathogenic ★★ same condition
SMCHD1 p.Arg1795Ter Pathogenic ★★ same condition
SMCHD1 p.Arg344Ter Pathogenic ★★ same condition
SMCHD1 p.Arg552Ter Pathogenic ★★ same condition
SMCHD1 p.Arg886Ter Pathogenic/Likely pathogenic ★★ same condition
SMCHD1 p.Gln1162Ter Pathogenic ★★ same condition
SMCHD1 p.Gln396Ter 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/smchd1-p-pro140 (accessed [today's date]).

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