Is MEF2C p.Val274= (c.822C>T) pathogenic?

MEF2C p.Val274= (c.822C>T) is classified Likely benign in MEF2C (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-08). Very rare (popmax 0.00541%, amr); Associated with Inborn genetic diseases.

What condition is associated with MEF2C p.Val274= (c.822C>T)?

MEF2C p.Val274= (c.822C>T) is associated with Inborn genetic diseases, neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (ClinVar).

How common is MEF2C p.Val274= (c.822C>T) in the general population?

MEF2C p.Val274= (c.822C>T) is very rare (popmax 0.00541%, amr) (gnomAD).

MEF2C p.Val274=

c.822C>T · rs1282449699 · VCV698438

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00541%, amr)

Conditions

Inborn genetic diseases

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 0.77	GERP -3.4, phastCons 1
Overall
CADD	8.904	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00541% Admixed American · 3/55,428 alleles

Filtering AF 0.00144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000698%

Overall 0.00101% 16/1,581,124 alleles · very rare exomes 13/1,428,984 · genomes 3/152,140 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00541%	18,476
Remaining individualsnot grpmax-eligible	0.00163%	61,292
African / African-American	0.00135%	74,302
European (non-Finnish)	0.000946%	105,670

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: MEF2C
Protein: p.Val274=
Coding: c.822C>T
MANE Select: NM_002397
dbSNP: rs1282449699
Type: single nucleotide variant
Location: chr5:88730223 (GRCh38)
Gene constraint: LOEUF 0.212 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.80
Residue 274: the 'beta domain' region

Full MEF2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language

Similar variants

MEF2C p.Val274fs Pathogenic ★ same residue
MEF2C c.638-1G>A Pathogenic/Likely pathogenic ★★ same condition
MEF2C c.638-2A>C Pathogenic ★★ same condition
MEF2C c.965-2A>G Pathogenic ★★ same condition
MEF2C c.-26C>T Pathogenic ★★ same condition
MEF2C c.-8C>T Pathogenic ★★ same condition
MEF2C p.Arg15Cys Pathogenic/Likely pathogenic ★★ same condition
MEF2C p.Arg15His 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/mef2c-p-val274 (accessed [today's date]).

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