Is MED12 p.Ala2= (c.6G>T) pathogenic?

MED12 p.Ala2= (c.6G>T) is classified Likely benign in MED12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). Very rare (popmax 0.00221%, amr); Associated with FG syndrome.

What condition is associated with MED12 p.Ala2= (c.6G>T)?

MED12 p.Ala2= (c.6G>T) is associated with FG syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is MED12 p.Ala2= (c.6G>T) in the general population?

MED12 p.Ala2= (c.6G>T) is very rare (popmax 0.00221%, amr) (gnomAD).

MED12 p.Ala2=

c.6G>T · rs1186607917 · VCV2901186

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00221%, amr)

Conditions

FG syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Overall
CADD	15.87	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% Admixed American · 1/45,320 alleles

Filtering AF 0.000242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000581% 7/1,204,950 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00221%	45,320
European (non-Finnish)	0.000672%	148,903

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.Ala2=
Coding: c.6G>T
MANE Select: NM_005120
dbSNP: rs1186607917
Type: single nucleotide variant
Location: chrX:71118760 (GRCh38)
Structure: AlphaFold pLDDT 65.80 · 3 PDB

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.Ala2Gly Uncertain significance ★ ⚠ same residue
OPA1 p.Trp2Ter Likely pathogenic ★ same residue
MED12 p.Ala2Val Uncertain significance ★ ⚠ same residue
OPA1 p.Trp2Leu 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

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-ala2 (accessed [today's date]).

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