Is SMCHD1 p.Ser522Arg (c.1566C>G) pathogenic?

SMCHD1 p.Ser522Arg (c.1566C>G) is classified Uncertain significance in SMCHD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-07-23). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1.

How common is SMCHD1 p.Ser522Arg (c.1566C>G) in the general population?

SMCHD1 p.Ser522Arg (c.1566C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMCHD1 p.Ser522Arg (c.1566C>G)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

SMCHD1 p.Ser522Arg

c.1566C>G · rs1555633547 · VCV497503

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 1% in SMCHD1
REVEL	0.332	indeterminate
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.25	donor loss · deltas
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 51 kb · p 2.2e-19 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMCHD1
Protein: p.Ser522Arg
Coding: c.1566C>G
MANE Select: NM_015295
dbSNP: rs1555633547
Type: single nucleotide variant
Location: chr18:2700837 (GRCh38)
Gene constraint: LOEUF 0.342 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.17 · 1 PDB
Residue 522: 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

Similar variants

SMCHD1 p.Ser522Asn Uncertain significance ★ ⚠ same residue
SMCHD1 c.1040+1G>A Pathogenic ★★ same type
SMCHD1 c.424+1G>A Pathogenic/Likely pathogenic ★★ same type
SMCHD1 p.Arg1423Ter Pathogenic/Likely pathogenic ★★ same type
SMCHD1 p.Arg1795Ter Pathogenic ★★ same type
SMCHD1 p.Arg344Ter Pathogenic ★★ same type
SMCHD1 p.Arg552Ter Pathogenic ★★ same type
SMCHD1 p.Arg886Ter Pathogenic/Likely pathogenic ★★ same type

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-ser522arg (accessed [today's date]).

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