Is MEGF8 p.Pro691= (c.2073G>A) pathogenic?

MEGF8 p.Pro691= (c.2073G>A) is classified Likely benign in MEGF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). Very rare (popmax 0.00343%, amr); Associated with MEGF8-related Carpenter syndrome.

What condition is associated with MEGF8 p.Pro691= (c.2073G>A)?

MEGF8 p.Pro691= (c.2073G>A) is associated with MEGF8-related Carpenter syndrome (ClinVar).

How common is MEGF8 p.Pro691= (c.2073G>A) in the general population?

MEGF8 p.Pro691= (c.2073G>A) is very rare (popmax 0.00343%, amr) (gnomAD).

MEGF8 p.Pro691=

c.2073G>A · rs199656818 · VCV2156750

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00343%, amr)

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 -6.6
Overall
CADD	1.273	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00343% Admixed American · 2/58,372 alleles

Filtering AF 0.00209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00185%

Overall 0.00251% 40/1,596,462 alleles · very rare exomes 34/1,444,208 · genomes 6/152,254 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00343%	29,186
European (non-Finnish)	0.00291%	34,413
East Asian	0.00225%	44,448
Remaining individualsnot grpmax-eligible	0.00162%	61,706
Finnishnot grpmax-eligible	0.00157%	63,516
African / African-American	0.00134%	74,622

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.Pro691=
Coding: c.2073G>A
MANE Select: NM_001271938
dbSNP: rs199656818
Type: single nucleotide variant
Location: chr19:42344809 (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.Pro691Leu 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-pro691 (accessed [today's date]).

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