Is MED12 p.Pro1817Ser (c.5449C>T) pathogenic?

MED12 p.Pro1817Ser (c.5449C>T) is classified Uncertain significance in MED12 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-06-06). AlphaMissense: likely benign (0.0873); Very rare (popmax 0.000112%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with MED12 p.Pro1817Ser (c.5449C>T)?

MED12 p.Pro1817Ser (c.5449C>T) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is MED12 p.Pro1817Ser (c.5449C>T) in the general population?

MED12 p.Pro1817Ser (c.5449C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about MED12 p.Pro1817Ser (c.5449C>T)?

AlphaMissense predicts likely benign (score 0.0873) — an in-silico prediction, not a clinical call.

MED12 p.Pro1817Ser

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.5449C>T · VCV3355518

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.0873	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -6.22	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 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 5,712 bp · p 4.1e-09 · regional, not allelic
Overall
CADD	22.7	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

Grpmax group 0.000112% European (non-Finnish) · 1/895,249 alleles

Overall 8.26e-05% 1/1,210,170 alleles · very rare exomes 1/1,097,503 · genomes 0/112,667 · joint denominator

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.Pro1817Ser
Coding: c.5449C>T
MANE Select: NM_005120
Type: single nucleotide variant
Location: chrX:71136927 (GRCh38)
Structure: AlphaFold pLDDT 65.80 · 3 PDB
Residue 1817: a UniProt-annotated variant site (in hdkr); the 'interaction with ctnnb1 and gli3' region; the 'disordered' 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

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

MED12 p.Arg1295His Pathogenic ★★ same condition
MED12 p.Arg961Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
MED12 p.Gln1974Ter Pathogenic ★★ same condition
MED12 c.4048-3C>T Uncertain significance ★★ same condition
MED12 c.5401-3C>A Uncertain significance ★★ same condition
MED12 c.736-3T>C Uncertain significance ★★ same condition
MED12 p.Ala1222Gly Uncertain significance ★★ ⚠ same condition
MED12 p.Ala1385Val Uncertain significance ★★ ⚠ 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-pro1817ser (accessed [today's date]).

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