Is SMCHD1 p.Pro440= (c.1320T>C) pathogenic?

SMCHD1 p.Pro440= (c.1320T>C) is classified Likely benign in SMCHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-08). Ultra-rare (popmax 0.0165%, mid); Associated with facioscapulohumeral muscular dystrophy 2.

What condition is associated with SMCHD1 p.Pro440= (c.1320T>C)?

SMCHD1 p.Pro440= (c.1320T>C) is associated with facioscapulohumeral muscular dystrophy 2 (ClinVar).

How common is SMCHD1 p.Pro440= (c.1320T>C) in the general population?

SMCHD1 p.Pro440= (c.1320T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Facioscapulohumeral dystrophy inherited?

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

SMCHD1 p.Pro440=

c.1320T>C · rs200156169 · VCV1127838

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 -1.5	GERP -4.7
Overall
CADD	6.204	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.00378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00422% 68/1,611,992 alleles · ultra-rare exomes 64/1,459,642 · genomes 4/152,350 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0128%	7,800
European (non-Finnish)	0.00484%	20,673
Admixed American	0.00167%	59,952
African / African-American	0.00133%	75,028

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.Pro440=
Coding: c.1320T>C
MANE Select: NM_015295
dbSNP: rs200156169
Type: single nucleotide variant
Location: chr18:2698019 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.17 · 1 PDB
Residue 440: an α-helix; 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
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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-pro440 (accessed [today's date]).

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