Is MEGF10 p.Ala826Val (c.2477C>T) pathogenic?

MEGF10 p.Ala826Val (c.2477C>T) is classified Uncertain significance in MEGF10 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: likely benign (0.0909); Ultra-rare (popmax 0.0165%, mid); Associated with MEGF10-related myopathy.

What condition is associated with MEGF10 p.Ala826Val (c.2477C>T)?

MEGF10 p.Ala826Val (c.2477C>T) is associated with MEGF10-related myopathy (ClinVar).

How common is MEGF10 p.Ala826Val (c.2477C>T) in the general population?

MEGF10 p.Ala826Val (c.2477C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MEGF10 p.Ala826Val (c.2477C>T)?

AlphaMissense predicts likely benign (score 0.0909) — an in-silico prediction, not a clinical call.

MEGF10 p.Ala826Val

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.2477C>T · rs150095036 · VCV539960

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0909 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

MEGF10-related myopathy

Computational evidence

Protein change
AlphaMissense	0.0909	likely benign
REVEL	0.341	indeterminate
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.26	constrained · MANE · 2,381 bp · p 0.00031 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0165% Middle Eastern · 1/6,068 alleles

Filtering AF 0.00893% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00837%

Overall 0.00831% 134/1,612,786 alleles · ultra-rare exomes 129/1,460,642 · genomes 5/152,144 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,068
European (non-Finnish)	0.0104%	9,588
East Asian	0.00669%	14,957
Admixed American	0.005%	19,984
South Asian	0.0022%	45,439
Remaining individualsnot grpmax-eligible	0.0016%	62,420
African / African-American	0.00134%	74,840

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.Ala826Val
Coding: c.2477C>T
MANE Select: NM_001256545
dbSNP: rs150095036
Type: single nucleotide variant
Location: chr5:127443112 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.73
Residue 826: the egf-like 15 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.Ala826Thr Uncertain significance ★ ⚠ same residue
MEGF10 p.Ala826= Likely benign ★ 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

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-ala826val (accessed [today's date]).

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