Is MEF2C p.Pro261Ser (c.781C>T) pathogenic?

MEF2C p.Pro261Ser (c.781C>T) is classified Uncertain significance in MEF2C (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-20). AlphaMissense: likely benign (0.1123); Very rare (popmax 8.48e-05%, nfe); Associated with MEF2C-related disorder.

What condition is associated with MEF2C p.Pro261Ser (c.781C>T)?

MEF2C p.Pro261Ser (c.781C>T) is associated with MEF2C-related disorder (ClinVar).

How common is MEF2C p.Pro261Ser (c.781C>T) in the general population?

MEF2C p.Pro261Ser (c.781C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about MEF2C p.Pro261Ser (c.781C>T)?

AlphaMissense predicts likely benign (score 0.1123) — an in-silico prediction, not a clinical call.

MEF2C p.Pro261Ser

c.781C>T · rs1278522595 · VCV2635204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1123 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MEF2C-related disorder

Computational evidence

Protein change
AlphaMissense	0.1123	likely benign
REVEL	0.188	benign-leaning
SaProt	LLR -7.36	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 39 kb · p 1.1e-22 · regional, not allelic
Overall
CADD	27.4	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 8.48e-05% European (non-Finnish) · 1/1,179,416 alleles

Overall 6.2e-05% 1/1,613,296 alleles · very rare exomes 1/1,461,060 · genomes 0/152,236 · 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: MEF2C
Protein: p.Pro261Ser
Coding: c.781C>T
MANE Select: NM_002397
dbSNP: rs1278522595
Type: single nucleotide variant
Location: chr5:88731758 (GRCh38)
Gene constraint: LOEUF 0.212 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.80

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

Disease context

MEF2C-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MEF2C c.-8C>T Pathogenic ★★ same condition
MEF2C p.His76Arg Uncertain significance ★★ ⚠ same condition
MEF2C p.Pro261fs Pathogenic ★ same residue
MEF2C c.402+163A>G Uncertain significance ★ same condition
MEF2C c.402+154T>A Uncertain significance same condition
MEF2C p.Leu277_Leu278insTer Pathogenic ★★ same condition
MEF2C c.54+1del Likely pathogenic ★ same condition
MEF2C p.Ile6fs 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-pro261ser (accessed [today's date]).

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