Is SMCHD1 p.Pro586Ser (c.1756C>T) pathogenic?

SMCHD1 p.Pro586Ser (c.1756C>T) is classified Uncertain significance in SMCHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely benign (0.074); Ultra-rare (popmax 0.0536%, eas); Associated with facioscapulohumeral muscular dystrophy 2.

What condition is associated with SMCHD1 p.Pro586Ser (c.1756C>T)?

SMCHD1 p.Pro586Ser (c.1756C>T) is associated with facioscapulohumeral muscular dystrophy 2 (ClinVar).

How common is SMCHD1 p.Pro586Ser (c.1756C>T) in the general population?

SMCHD1 p.Pro586Ser (c.1756C>T) is ultra-rare (popmax 0.0536%, eas) (gnomAD).

How is Facioscapulohumeral dystrophy inherited?

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

What do computational predictors say about SMCHD1 p.Pro586Ser (c.1756C>T)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

SMCHD1 p.Pro586Ser

c.1756C>T · VCV3722030

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0536%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

facioscapulohumeral muscular dystrophy 2

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -6.18	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 0.92	GERP -0.38, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 51 kb · p 2.2e-19 · regional, not allelic
Overall
CADD	14.83	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 0.0536% East Asian · 24/44,796 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.00205% 33/1,612,794 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0536%	1,867
Finnishnot grpmax-eligible	0.00781%	12,798
European (non-Finnish)	0.000339%	294,815

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.Pro586Ser
Coding: c.1756C>T
MANE Select: NM_015295
Type: single nucleotide variant
Location: chr18:2703800 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.17 · 1 PDB
Residue 586: 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 p.Pro586Leu Uncertain significance ★ ⚠ same residue
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

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-pro586ser (accessed [today's date]).

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