Is MEGF10 p.Arg89Ser (c.267G>T) pathogenic?

MEGF10 p.Arg89Ser (c.267G>T) is classified Uncertain significance in MEGF10 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-04). AlphaMissense: likely pathogenic (0.9216); Very rare (popmax 0.000933%, nfe); Associated with MEGF10-related myopathy.

What condition is associated with MEGF10 p.Arg89Ser (c.267G>T)?

MEGF10 p.Arg89Ser (c.267G>T) is associated with MEGF10-related myopathy (ClinVar).

How common is MEGF10 p.Arg89Ser (c.267G>T) in the general population?

MEGF10 p.Arg89Ser (c.267G>T) is very rare (popmax 0.000933%, nfe) (gnomAD).

What do computational predictors say about MEGF10 p.Arg89Ser (c.267G>T)?

AlphaMissense predicts likely pathogenic (score 0.9216) — an in-silico prediction, not a clinical call.

MEGF10 p.Arg89Ser

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.267G>T · rs368073107 · VCV539966

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9216 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000933%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

MEGF10-related myopathy

Computational evidence

Protein change
AlphaMissense	0.9216	likely pathogenic
REVEL	0.405	indeterminate
SaProt	LLR -12.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP -1.1, phastCons 0.98
Regional constraint	o/e 0.90	unconstrained · MANE · 112 kb · p 0.0013 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000933% European (non-Finnish) · 11/1,179,200 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,612,968 alleles · very rare exomes 11/1,460,712 · genomes 0/152,256 · joint denominator

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.Arg89Ser
Coding: c.267G>T
MANE Select: NM_001256545
dbSNP: rs368073107
Type: single nucleotide variant
Location: chr5:127340578 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.73
Residue 89: the 'necessary for interaction with ap2m1, self-assembly and formation of the irregular, mosaic-like adhesion pattern' region; the emi domain

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 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
MEGF10 p.Ala219Val 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-arg89ser (accessed [today's date]).

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