Is MED12 p.Val1985Ile (c.5953G>A) pathogenic?

MED12 p.Val1985Ile (c.5953G>A) is classified Uncertain significance in MED12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-02). AlphaMissense: likely benign (0.0825); Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with MED12 p.Val1985Ile (c.5953G>A)?

MED12 p.Val1985Ile (c.5953G>A) is associated with familial thoracic aortic aneurysm and aortic dissection, FG syndrome (ClinVar).

How common is MED12 p.Val1985Ile (c.5953G>A) in the general population?

MED12 p.Val1985Ile (c.5953G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MED12 p.Val1985Ile (c.5953G>A)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

MED12 p.Val1985Ile

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.5953G>A · rs2519715718 · VCV3224594

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.78, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 5,712 bp · p 4.1e-09 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MED12
Protein: p.Val1985Ile
Coding: c.5953G>A
MANE Select: NM_005120
dbSNP: rs2519715718
Type: single nucleotide variant
Location: chrX:71137852 (GRCh38)
Structure: AlphaFold pLDDT 65.80 · 3 PDB
Residue 1985: 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

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.Val1985Glu Uncertain significance ★ ⚠ same residue
MED12 p.Val1985Ala 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

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-val1985ile (accessed [today's date]).

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