Is SMCHD1 p.Pro808= (c.2424A>G) pathogenic?

SMCHD1 p.Pro808= (c.2424A>G) is classified Likely benign in SMCHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-23). Very rare (popmax 0.00136%, nfe); Associated with facioscapulohumeral muscular dystrophy 2.

What condition is associated with SMCHD1 p.Pro808= (c.2424A>G)?

SMCHD1 p.Pro808= (c.2424A>G) is associated with facioscapulohumeral muscular dystrophy 2 (ClinVar).

How common is SMCHD1 p.Pro808= (c.2424A>G) in the general population?

SMCHD1 p.Pro808= (c.2424A>G) is very rare (popmax 0.00136%, nfe) (gnomAD).

How is Facioscapulohumeral dystrophy inherited?

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

SMCHD1 p.Pro808=

c.2424A>G · rs374039360 · VCV3021044

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00136%, 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 -0.17	GERP -1.7, phastCons 0.003
Overall
CADD	4.111	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,178,858 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00105% 17/1,611,956 alleles · very rare exomes 14/1,459,714 · genomes 3/152,242 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00136%	73,678
South Asian	0.0011%	90,610

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.Pro808=
Coding: c.2424A>G
MANE Select: NM_015295
dbSNP: rs374039360
Type: single nucleotide variant
Location: chr18:2718400 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.17 · 1 PDB
Residue 808: a UniProt-annotated variant site (in fshd2)

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-pro808 (accessed [today's date]).

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