Is MEGF8 p.Asp90= (c.270C>T) pathogenic?

MEGF8 p.Asp90= (c.270C>T) is classified Likely benign in MEGF8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-09). Ultra-rare (popmax 0.024%, afr); Associated with MEGF8-related Carpenter syndrome.

What condition is associated with MEGF8 p.Asp90= (c.270C>T)?

MEGF8 p.Asp90= (c.270C>T) is associated with MEGF8-related Carpenter syndrome (ClinVar).

How common is MEGF8 p.Asp90= (c.270C>T) in the general population?

MEGF8 p.Asp90= (c.270C>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

MEGF8 p.Asp90=

c.270C>T · rs376175890 · VCV3037239

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

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 -20
Overall
CADD	0.154	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/74,932 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00545% 88/1,613,892 alleles · ultra-rare exomes 70/1,461,660 · genomes 18/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,163
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.00961%	10,411
European (non-Finnish)	0.00475%	21,070
East Asian	0.00445%	22,448
Admixed American	0.00333%	30,001
South Asian	0.00329%	30,363

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.Asp90=
Coding: c.270C>T
MANE Select: NM_001271938
dbSNP: rs376175890
Type: single nucleotide variant
Location: chr19:42333687 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI <0.01 (gnomAD)
Residue 90: the cub 1 domain

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-asp90 (accessed [today's date]).

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