Is SGMS2 p.Phe239fs (c.714_715insAT) pathogenic?

SGMS2 p.Phe239fs (c.714715insAT) is classified Uncertain significance in SGMS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-17). Ultra-rare (popmax 0.0123%, nfe); Associated with calvarial doughnut lesions-bone fragility syndrome.

What condition is associated with SGMS2 p.Phe239fs (c.714_715insAT)?

SGMS2 p.Phe239fs (c.714_715insAT) is associated with calvarial doughnut lesions-bone fragility syndrome (ClinVar).

How common is SGMS2 p.Phe239fs (c.714_715insAT) in the general population?

SGMS2 p.Phe239fs (c.714_715insAT) is ultra-rare (popmax 0.0123%, nfe) (gnomAD).

SGMS2 p.Phe239fs

c.714_715insAT · rs779248083 · VCV2171606

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Conditions

calvarial doughnut lesions-bone fragility syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 6.6	GERP 2, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0123% European (non-Finnish) · 145/1,179,854 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00997%

Overall 0.0108% 174/1,613,680 alleles · ultra-rare exomes 167/1,461,554 · genomes 7/152,126 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.04%	2,499
European (non-Finnish)grpmax	0.0123%	8,137
Admixed American	0.00667%	14,987

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe239fs
Coding: c.714_715insAT
MANE Select: NM_001375905
dbSNP: rs779248083
Type: Insertion
Location: chr4:107903373 (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-phe239fs (accessed [today's date]).

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