Is MEF2C p.Leu45Pro (c.134T>C) pathogenic?

MEF2C p.Leu45Pro (c.134T>C) is classified Likely pathogenic in MEF2C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-04). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language.

How common is MEF2C p.Leu45Pro (c.134T>C) in the general population?

MEF2C p.Leu45Pro (c.134T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MEF2C p.Leu45Pro (c.134T>C)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

MEF2C p.Leu45Pro

Q: What condition is associated with MEF2C p.Leu45Pro (c.134T>C)?

MEF2C p.Leu45Pro (c.134T>C) is associated with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (ClinVar).

c.134T>C · rs2531283403 · VCV2692484

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic ✓ concordant with ClinVar · top 7% in MEF2C
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -14.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.15	constrained · MANE · 63 kb · p 1.7e-23 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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: MEF2C
Protein: p.Leu45Pro
Coding: c.134T>C
MANE Select: NM_002397
dbSNP: rs2531283403
Type: single nucleotide variant
Location: chr5:88804722 (GRCh38)
Gene constraint: LOEUF 0.212 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.80
Residue 45: the mads-box domain

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

Disease context

neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
MEF2C p.Arg15Pro 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-leu45pro (accessed [today's date]).

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