Is MEGF8 p.Pro786Arg (c.2357C>G) pathogenic?

MEGF8 p.Pro786Arg (c.2357C>G) is classified Conflicting classifications of pathogenicity in MEGF8 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-13). AlphaMissense: likely benign (0.1047); Rare (popmax 0.217%, afr); Associated with MEGF8-related Carpenter syndrome.

What condition is associated with MEGF8 p.Pro786Arg (c.2357C>G)?

MEGF8 p.Pro786Arg (c.2357C>G) is associated with MEGF8-related Carpenter syndrome (ClinVar).

How common is MEGF8 p.Pro786Arg (c.2357C>G) in the general population?

MEGF8 p.Pro786Arg (c.2357C>G) is rare (popmax 0.217%, afr) (gnomAD).

What do computational predictors say about MEGF8 p.Pro786Arg (c.2357C>G)?

AlphaMissense predicts likely benign (score 0.1047) — an in-silico prediction, not a clinical call.

MEGF8 p.Pro786Arg

c.2357C>G · rs114954140 · VCV1335841

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1047 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.217%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

MEGF8-related Carpenter syndrome

Computational evidence

Protein change
AlphaMissense	0.1047	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 51 kb · p 7.6e-23 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.217% African / African-American · 163/75,026 alleles

Filtering AF 0.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.18%

Overall 0.0112% 180/1,612,102 alleles · rare exomes 85/1,459,832 · genomes 95/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.217%	460
Remaining individualsnot grpmax-eligible	0.0192%	5,203
Middle Eastern	0.0167%	6,004
Admixed American	0.00333%	30,011
European (non-Finnish)	0.00017%	589,915

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: MEGF8
Protein: p.Pro786Arg
Coding: c.2357C>G
MANE Select: NM_001271938
dbSNP: rs114954140
Type: single nucleotide variant
Location: chr19:42349557 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI <0.01 (gnomAD)

Full MEGF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MEGF8-related Carpenter syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MEGF8 p.Arg419Ter Pathogenic/Likely pathogenic ★★ same condition
MEGF8 p.Arg991Ter Pathogenic/Likely pathogenic ★★ same condition
MEGF8 p.Ala1472Val Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala1572Thr Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala176Gly Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala1791Ser Uncertain significance ★★ same condition
MEGF8 p.Ala2104Ser Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala2349Gly 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/megf8-p-pro786arg (accessed [today's date]).

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