Is MEGF10 p.Pro269= (c.807C>T) pathogenic?

MEGF10 p.Pro269= (c.807C>T) is classified Likely benign in MEGF10 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-28). Ultra-rare (popmax 0.024%, afr); Associated with MEGF10-related myopathy.

What condition is associated with MEGF10 p.Pro269= (c.807C>T)?

MEGF10 p.Pro269= (c.807C>T) is associated with MEGF10-related myopathy (ClinVar).

How common is MEGF10 p.Pro269= (c.807C>T) in the general population?

MEGF10 p.Pro269= (c.807C>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

MEGF10 p.Pro269=

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.807C>T · rs146742773 · VCV385086

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Conditions

MEGF10-related myopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -3.4
Overall
CADD	0.385	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/74,994 alleles

Filtering AF 0.0192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0183%

Overall 0.0177% 285/1,613,966 alleles · ultra-rare exomes 257/1,461,738 · genomes 28/152,228 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,166
European (non-Finnish)	0.0214%	4,682
Middle Eastern	0.0165%	6,058
Admixed American	0.01%	9,998
Remaining individualsnot grpmax-eligible	0.008%	12,502
South Asian	0.0022%	45,530
Finnishnot grpmax-eligible	0.00156%	64,022

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.Pro269=
Coding: c.807C>T
MANE Select: NM_001256545
dbSNP: rs146742773
Type: single nucleotide variant
Location: chr5:127402572 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.73
Residue 269: 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.Pro269Leu 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
MEGF10 p.Ala171Thr Uncertain significance ★★ ⚠ same condition
MEGF10 p.Ala171Val 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-pro269 (accessed [today's date]).

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