Is MEGF8 p.Cys2001= (c.6003C>T) pathogenic?

MEGF8 p.Cys2001= (c.6003C>T) is classified Conflicting classifications of pathogenicity in MEGF8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-02-24). Very rare (popmax 0.00549%, sas); Associated with MEGF8-related Carpenter syndrome.

What condition is associated with MEGF8 p.Cys2001= (c.6003C>T)?

MEGF8 p.Cys2001= (c.6003C>T) is associated with MEGF8-related Carpenter syndrome (ClinVar).

How common is MEGF8 p.Cys2001= (c.6003C>T) in the general population?

MEGF8 p.Cys2001= (c.6003C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

MEGF8 p.Cys2001=

c.6003C>T · rs536661123 · VCV1023184

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

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 -8.6
Overall
CADD	3.33	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,084 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00248% 40/1,613,540 alleles · very rare exomes 38/1,461,196 · genomes 2/152,344 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,217
African / African-American	0.00533%	18,763
European (non-Finnish)	0.00254%	39,330
Admixed American	0.00167%	60,030

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.Cys2001=
Coding: c.6003C>T
MANE Select: NM_001271938
dbSNP: rs536661123
Type: single nucleotide variant
Location: chr19:42362542 (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-cys2001 (accessed [today's date]).

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