Is SGMS2 p.Pro57= (c.171G>A) pathogenic?

SGMS2 p.Pro57= (c.171G>A) is classified Benign/Likely benign in SGMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-14). Low-frequency (popmax 1.19%, afr); Associated with calvarial doughnut lesions-bone fragility syndrome.

What condition is associated with SGMS2 p.Pro57= (c.171G>A)?

SGMS2 p.Pro57= (c.171G>A) is associated with calvarial doughnut lesions-bone fragility syndrome (ClinVar).

How common is SGMS2 p.Pro57= (c.171G>A) in the general population?

SGMS2 p.Pro57= (c.171G>A) is low-frequency (popmax 1.19%, afr) (gnomAD).

SGMS2 p.Pro57=

c.171G>A · rs150784082 · VCV1595949

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.19%, afr)

Conditions

calvarial doughnut lesions-bone fragility syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -14	GERP -5.6
Overall
CADD	0.713	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.19% African / African-American · 892/74,982 alleles

Filtering AF 1.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1%

Overall 0.0712% 1,149/1,613,862 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.19%	84
Remaining individualsnot grpmax-eligible	0.106%	947
Admixed American	0.1%	999
Middle Eastern	0.0165%	6,058
European (non-Finnish)	0.0103%	9,752
East Asian	0.00669%	14,943
South Asian	0.00659%	15,179

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: SGMS2
Protein: p.Pro57=
Coding: c.171G>A
MANE Select: NM_001375905
dbSNP: rs150784082
Type: single nucleotide variant
Location: chr4:107895724 (GRCh38)

Full SGMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

calvarial doughnut lesions-bone fragility syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/sgms2-p-pro57 (accessed [today's date]).

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