Is MEGF10 p.Pro552Ser (c.1654C>T) pathogenic?

MEGF10 p.Pro552Ser (c.1654C>T) is classified Uncertain significance in MEGF10 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.1105); Very rare (popmax 0.000424%, nfe); Associated with MEGF10-related myopathy.

What condition is associated with MEGF10 p.Pro552Ser (c.1654C>T)?

MEGF10 p.Pro552Ser (c.1654C>T) is associated with MEGF10-related myopathy (ClinVar).

How common is MEGF10 p.Pro552Ser (c.1654C>T) in the general population?

MEGF10 p.Pro552Ser (c.1654C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about MEGF10 p.Pro552Ser (c.1654C>T)?

AlphaMissense predicts likely benign (score 0.1105) — an in-silico prediction, not a clinical call.

MEGF10 p.Pro552Ser

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.1654C>T · rs978960737 · VCV539957

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MEGF10-related myopathy

Computational evidence

Protein change
AlphaMissense	0.1105	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -9.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP -1.1, phastCons 0.045
Regional constraint	o/e 0.90	unconstrained · MANE · 112 kb · p 0.0013 · regional, not allelic
Overall
CADD	14.82	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 0.000424% European (non-Finnish) · 5/1,180,012 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,990 alleles · very rare exomes 1/1,461,832 · genomes 6/152,158 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.219%	456
European (non-Finnish)grpmax	0.000424%	236,002

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro552Ser
Coding: c.1654C>T
MANE Select: NM_001256545
dbSNP: rs978960737
Type: single nucleotide variant
Location: chr5:127422733 (GRCh38)
Gene constraint: LOEUF 0.707 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.73
Residue 552: the egf-like 10 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 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-pro552ser (accessed [today's date]).

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