Is MEGF10 p.Pro692= (c.2076C>T) pathogenic?

MEGF10 p.Pro692= (c.2076C>T) is classified Benign/Likely benign in MEGF10 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). Common (popmax 5.91%, afr) — too common for a highly-penetrant pathogenic allele; Associated with MEGF10-related myopathy.

What condition is associated with MEGF10 p.Pro692= (c.2076C>T)?

MEGF10 p.Pro692= (c.2076C>T) is associated with MEGF10-related myopathy (ClinVar).

MEGF10 p.Pro692=

Q: How common is MEGF10 p.Pro692= (c.2076C>T) in the general population?

MEGF10 p.Pro692= (c.2076C>T) is common (popmax 5.91%, 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.2076C>T · rs115309591 · VCV262068

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 5.91%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -10	GERP -3.5
Overall
CADD	0.342	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.91% African / African-American · 4,429/74,944 alleles

Filtering AF 5.76% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.71%

Overall 0.31% 5,003/1,613,784 alleles · common exomes 2,456/1,461,600 · genomes 2,547/152,184 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.91%	17
Admixed American	0.39%	256
Remaining individualsnot grpmax-eligible	0.366%	273
Middle Eastern	0.165%	606
South Asian	0.0176%	5,689
European (non-Finnish)	0.0072%	13,881

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.Pro692=
Coding: c.2076C>T
MANE Select: NM_001256545
dbSNP: rs115309591
Type: single nucleotide variant
Location: chr5:127435461 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.73
Residue 692: the egf-like 12 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.Pro692Thr 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-pro692 (accessed [today's date]).

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