Is MEGF10 p.Pro487Arg (c.1460C>G) pathogenic?

MEGF10 p.Pro487Arg (c.1460C>G) is classified Uncertain significance in MEGF10 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-02). AlphaMissense: likely benign (0.1507); Absent from gnomAD v4.1; Associated with MEGF10-related myopathy.

What condition is associated with MEGF10 p.Pro487Arg (c.1460C>G)?

MEGF10 p.Pro487Arg (c.1460C>G) is associated with MEGF10-related myopathy (ClinVar).

How common is MEGF10 p.Pro487Arg (c.1460C>G) in the general population?

MEGF10 p.Pro487Arg (c.1460C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MEGF10 p.Pro487Arg (c.1460C>G)?

AlphaMissense predicts likely benign (score 0.1507) — an in-silico prediction, not a clinical call.

MEGF10 p.Pro487Arg

Q: How is Early-onset myopathy-areflexia-respiratory distress-dysphagia syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1460C>G · rs376778102 · VCV1053262

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1507 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MEGF10-related myopathy

Computational evidence

Protein change
AlphaMissense	0.1507	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -10.32	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 112 kb · p 0.0013 · regional, not allelic
Overall
CADD	24.7	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: MEGF10
Protein: p.Pro487Arg
Coding: c.1460C>G
MANE Select: NM_001256545
dbSNP: rs376778102
Type: single nucleotide variant
Location: chr5:127420077 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.73
Residue 487: the 'necessary for interaction with ap2m1, self-assembly and formation of the irregular, mosaic-like adhesion pattern' region

Full MEGF10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MEGF10-related myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early-onset myopathy-areflexia-respiratory distress-dysphagia syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

MEGF10 c.2104+1G>T Likely pathogenic ★★ same condition
MEGF10 p.Cys774Arg Pathogenic/Likely pathogenic ★★ same condition
MEGF10 p.Glu398Ter Pathogenic/Likely pathogenic ★★ same condition
MEGF10 c.1426+5G>T Uncertain significance ★★ same condition
MEGF10 c.*1170G>A Uncertain significance ★★ same condition
MEGF10 p.Ala171Thr Uncertain significance ★★ ⚠ same condition
MEGF10 p.Ala171Val Uncertain significance ★★ ⚠ same condition
MEGF10 p.Ala219Val Uncertain significance ★★ ⚠ 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/megf10-p-pro487arg (accessed [today's date]).

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