Is MED12 p.Met2026Val (c.6076A>G) pathogenic?

MED12 p.Met2026Val (c.6076A>G) is classified Uncertain significance in MED12 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-18). AlphaMissense: likely benign (0.0795); Very rare (popmax 0.0022%, amr); Associated with FG syndrome.

What condition is associated with MED12 p.Met2026Val (c.6076A>G)?

MED12 p.Met2026Val (c.6076A>G) is associated with FG syndrome, blepharophimosis - intellectual disability syndrome, MKB type, FG syndrome 1 (ClinVar).

How common is MED12 p.Met2026Val (c.6076A>G) in the general population?

MED12 p.Met2026Val (c.6076A>G) is very rare (popmax 0.0022%, amr) (gnomAD).

What do computational predictors say about MED12 p.Met2026Val (c.6076A>G)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

MED12 p.Met2026Val

c.6076A>G · rs1294140756 · VCV1360673

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FG syndrome

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -5.84	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 8.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 5,712 bp · p 4.1e-09 · regional, not allelic
Overall
CADD	18.96	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 0.0022% Admixed American · 1/45,421 alleles

Filtering AF 0.00066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000482%

Overall 0.000993% 12/1,208,253 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0022%	45,421
European (non-Finnish)	0.00123%	81,349

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.Met2026Val
Coding: c.6076A>G
MANE Select: NM_005120
dbSNP: rs1294140756
Type: single nucleotide variant
Location: chrX:71140666 (GRCh38)
Structure: AlphaFold pLDDT 65.80 · 3 PDB
Residue 2026: 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: blepharophimosis - intellectual disability syndrome, MKB type FG syndrome 1 X-linked intellectual disability with marfanoid habitus cholestasis-pigmentary retinopathy-cleft palate syndrome familial thoracic aortic aneurysm and aortic dissection

Similar variants

MED12 p.Met2026Ile Likely benign ★ same residue
MED12 p.Met2026del Uncertain significance ★ same residue
MED12 c.6408+1G>A Pathogenic/Likely pathogenic ★★ same condition
MED12 p.Ala1169Ser Likely pathogenic ★★ ⚠ same condition
MED12 p.Arg1138Trp 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-met2026val (accessed [today's date]).

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