Is MED12 p.Ser1925= (c.5775A>G) pathogenic?

MED12 p.Ser1925= (c.5775A>G) is classified Benign/Likely benign in MED12 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-17). Ultra-rare (popmax 0.0125%, nfe); Associated with FG syndrome.

What condition is associated with MED12 p.Ser1925= (c.5775A>G)?

MED12 p.Ser1925= (c.5775A>G) is associated with FG syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is MED12 p.Ser1925= (c.5775A>G) in the general population?

MED12 p.Ser1925= (c.5775A>G) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

MED12 p.Ser1925=

c.5775A>G · rs376753995 · VCV379562

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Conditions

FG syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.033	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.43	GERP -0.68, phastCons 0.68
Overall
CADD	6.781	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0125% European (non-Finnish) · 112/893,904 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00992%

Overall 0.00969% 117/1,207,891 alleles · ultra-rare exomes 112/1,096,562 · genomes 5/111,329 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	7,981
Remaining individualsnot grpmax-eligible	0.00842%	11,878
African / African-American	0.00176%	56,964

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: MED12
Protein: p.Ser1925=
Coding: c.5775A>G
MANE Select: NM_005120
dbSNP: rs376753995
Type: single nucleotide variant
Location: chrX:71137584 (GRCh38)
Structure: AlphaFold pLDDT 65.80 · 3 PDB
Residue 1925: the 'disordered' region; a UniProt-annotated variant site (in hdkr); the 'interaction with ctnnb1 and gli3' region

Full MED12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

FG syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

MED12 p.Ser1925Pro Uncertain significance ★ ⚠ same residue
MED12 c.6408+1G>A Pathogenic/Likely pathogenic ★★ same condition
MED12 p.Arg1295Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
MED12 p.Arg1295His Pathogenic ★★ same condition
MED12 p.Arg1357His Pathogenic/Likely pathogenic ★★ ⚠ same condition
MED12 p.Arg296Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
MED12 p.Arg961Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
MED12 p.Asn1007Ser Pathogenic/Likely 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/med12-p-ser1925 (accessed [today's date]).

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