Is MEGF8 p.Pro499= (c.1497G>A) pathogenic?

MEGF8 p.Pro499= (c.1497G>A) is classified Likely benign in MEGF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-25). Ultra-rare (popmax 0.0168%, mid); Associated with MEGF8-related Carpenter syndrome.

What condition is associated with MEGF8 p.Pro499= (c.1497G>A)?

MEGF8 p.Pro499= (c.1497G>A) is associated with MEGF8-related Carpenter syndrome (ClinVar).

How common is MEGF8 p.Pro499= (c.1497G>A) in the general population?

MEGF8 p.Pro499= (c.1497G>A) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

MEGF8 p.Pro499=

c.1497G>A · rs374205876 · VCV2141462

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Conditions

MEGF8-related Carpenter syndrome

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 -12
Overall
CADD	0.47	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% Middle Eastern · 1/5,936 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00483% 78/1,613,634 alleles · ultra-rare exomes 69/1,461,490 · genomes 9/152,144 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,936
South Asian	0.011%	9,106
European (non-Finnish)	0.00525%	19,030
Remaining individualsnot grpmax-eligible	0.0048%	20,813
East Asian	0.00223%	44,892
African / African-American	0.00133%	74,916

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.Pro499=
Coding: c.1497G>A
MANE Select: NM_001271938
dbSNP: rs374205876
Type: single nucleotide variant
Location: chr19:42337190 (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.Pro499Leu Uncertain significance ★ ⚠ same residue
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

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-pro499 (accessed [today's date]).

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