Is MEF2D p.Pro499Arg (c.1496C>G) pathogenic?

MEF2D p.Pro499Arg (c.1496C>G) is classified Uncertain significance in MEF2D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-20). AlphaMissense: likely benign (0.2458); Absent from gnomAD v4.1.

How common is MEF2D p.Pro499Arg (c.1496C>G) in the general population?

MEF2D p.Pro499Arg (c.1496C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MEF2D p.Pro499Arg (c.1496C>G)?

AlphaMissense predicts likely benign (score 0.2458) — an in-silico prediction, not a clinical call.

MEF2D p.Pro499Arg

c.1496C>G · VCV3294087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2458 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2458	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
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 0.82	unconstrained · MANE · 15 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	26.2	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

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: MEF2D
Protein: p.Pro499Arg
Coding: c.1496C>G
MANE Select: NM_005920
Type: single nucleotide variant
Location: chr1:156468051 (GRCh38)
Gene constraint: LOEUF 0.285 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.81 · 2 PDB
Residue 499: the 'disordered' region

Full MEF2D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MEF2D p.Ala200Pro Uncertain significance ★ ⚠ same type
MEF2D p.Ala452Val Uncertain significance ★ ⚠ same type
MEF2D p.Arg24Gln Uncertain significance ★ ⚠ same type
MEF2D p.Arg487Gln Uncertain significance ★ ⚠ same type
MEF2D p.Arg487Trp Uncertain significance ★ ⚠ same type
MEF2D p.Asn241Asp Uncertain significance ★ ⚠ same type
MEF2D p.Asn52Lys Uncertain significance ★ ⚠ same type
MEF2D p.Asp97Asn Uncertain significance ★ ⚠ same type

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/mef2d-p-pro499arg (accessed [today's date]).

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