Is MEGF10 p.Arg306Gln (c.917G>A) pathogenic?

MEGF10 p.Arg306Gln (c.917G>A) is classified Conflicting classifications of pathogenicity in MEGF10 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-03). AlphaMissense: likely benign (0.2127); Ultra-rare (popmax 0.012%, afr); Associated with MEGF10-related myopathy.

What condition is associated with MEGF10 p.Arg306Gln (c.917G>A)?

MEGF10 p.Arg306Gln (c.917G>A) is associated with MEGF10-related myopathy (ClinVar).

How common is MEGF10 p.Arg306Gln (c.917G>A) in the general population?

MEGF10 p.Arg306Gln (c.917G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about MEGF10 p.Arg306Gln (c.917G>A)?

AlphaMissense predicts likely benign (score 0.2127) — an in-silico prediction, not a clinical call.

MEGF10 p.Arg306Gln

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>A · rs986353158 · VCV1314583

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2127 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MEGF10-related myopathy

Computational evidence

Protein change
AlphaMissense	0.2127	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -7.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.72	donor loss · deltas
Pangolin	Δ0.63	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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,892 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00105% 17/1,613,690 alleles · ultra-rare exomes 11/1,461,490 · genomes 6/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,321
Admixed American	0.00334%	29,978
Remaining individualsnot grpmax-eligible	0.0016%	62,474
South Asian	0.0011%	91,004
European (non-Finnish)	0.000339%	294,969

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.Arg306Gln
Coding: c.917G>A
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.Arg306Pro Uncertain significance ★ ⚠ 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-arg306gln (accessed [today's date]).

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