Is MED12 p.Phe877= (c.2631C>T) pathogenic?

MED12 p.Phe877= (c.2631C>T) is classified Likely benign in MED12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-18). Very rare (popmax 0.00174%, afr); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with MED12 p.Phe877= (c.2631C>T)?

MED12 p.Phe877= (c.2631C>T) is associated with familial thoracic aortic aneurysm and aortic dissection, FG syndrome (ClinVar).

How common is MED12 p.Phe877= (c.2631C>T) in the general population?

MED12 p.Phe877= (c.2631C>T) is very rare (popmax 0.00174%, afr) (gnomAD).

MED12 p.Phe877=

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.2631C>T · rs751190759 · VCV1086094

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00174%, afr)

Conditions

familial thoracic aortic aneurysm and aortic dissection

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 -2.7	GERP -3.8
Overall
CADD	6.669	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00174% African / African-American · 1/57,442 alleles

Filtering AF 0.000907% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00071%

Overall 0.00124% 15/1,210,716 alleles · very rare exomes 14/1,097,955 · genomes 1/112,761 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00174%	57,442
European (non-Finnish)	0.00156%	63,945

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.Phe877=
Coding: c.2631C>T
MANE Select: NM_005120
dbSNP: rs751190759
Type: single nucleotide variant
Location: chrX:71126430 (GRCh38)
Structure: AlphaFold pLDDT 65.80 · 3 PDB
Residue 877: a UniProt-annotated variant site (in hdkr)

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

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: FG syndrome

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

MED12 p.Phe877Leu 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-phe877 (accessed [today's date]).

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