Is MEGF10 p.Pro595= (c.1785T>C) pathogenic?

MEGF10 p.Pro595= (c.1785T>C) is classified Benign in MEGF10 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). Common (popmax 30.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with MEGF10-related myopathy.

What condition is associated with MEGF10 p.Pro595= (c.1785T>C)?

MEGF10 p.Pro595= (c.1785T>C) is associated with MEGF10-related myopathy (ClinVar).

MEGF10 p.Pro595=

Q: How common is MEGF10 p.Pro595= (c.1785T>C) in the general population?

MEGF10 p.Pro595= (c.1785T>C) is common (popmax 30.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1785T>C · rs11950427 · VCV262065

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 30.1%, afr) — too common for a highly-penetrant pathogenic allele

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 -20	GERP -3.7
Overall
CADD	0.005	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 30.1% African / African-American · 22,591/74,944 alleles

Filtering AF 29.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 29.7%

Overall 15.8% 254,880/1,613,632 alleles · common exomes 225,620/1,461,468 · genomes 29,260/152,164 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	30.1%	3
Finnishnot grpmax-eligible	19%	5
South Asian	17.6%	6
Remaining individualsnot grpmax-eligible	15.2%	7
European (non-Finnish)	15.2%	7
Ashkenazi Jewishnot grpmax-eligible	14.3%	7
Amishnot grpmax-eligible	13.9%	7
Middle Eastern	12.1%	8
East Asian	11%	9
Admixed American	9.25%	11

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.Pro595=
Coding: c.1785T>C
MANE Select: NM_001256545
dbSNP: rs11950427
Type: single nucleotide variant
Location: chr5:127433454 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.73
Residue 595: the egf-like 11 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.Pro595Ala 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-pro595 (accessed [today's date]).

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