Is MEGF10 p.Arg306Pro (c.917G>C) pathogenic?

MEGF10 p.Arg306Pro (c.917G>C) is classified Uncertain significance in MEGF10 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-21). AlphaMissense: likely pathogenic (0.9683); Very rare (popmax 0.00133%, afr); Associated with MEGF10-related myopathy.

What condition is associated with MEGF10 p.Arg306Pro (c.917G>C)?

MEGF10 p.Arg306Pro (c.917G>C) is associated with MEGF10-related myopathy (ClinVar).

How common is MEGF10 p.Arg306Pro (c.917G>C) in the general population?

MEGF10 p.Arg306Pro (c.917G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MEGF10 p.Arg306Pro (c.917G>C)?

AlphaMissense predicts likely pathogenic (score 0.9683) — an in-silico prediction, not a clinical call.

MEGF10 p.Arg306Pro

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.917G>C · rs986353158 · VCV1948946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9683 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

MEGF10-related myopathy

Computational evidence

Protein change
AlphaMissense	0.9683	likely pathogenic
REVEL	0.595	indeterminate
SaProt	LLR -14.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.55	donor loss · deltas
Pangolin	Δ0.68	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 0.93, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 112 kb · p 0.0013 · regional, not allelic
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/75,014 alleles

Overall 0.000124% 2/1,613,808 alleles · very rare exomes 2/1,461,490 · genomes 0/152,318 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,014
European (non-Finnish)	8.48e-05%	1,179,866

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: MEGF10
Protein: p.Arg306Pro
Coding: c.917G>C
MANE Select: NM_001256545
dbSNP: rs986353158
Type: single nucleotide variant
Location: chr5:127402682 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.73
Residue 306: the egf-like 5 domain; 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 p.Arg306Trp Uncertain significance ★★ ⚠ same residue
MEGF10 p.Arg306= Likely benign ★★ same residue
MEGF10 p.Arg306Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg306pro (accessed [today's date]).

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