Is MEGF8 p.Ala2829Val (c.8486C>T) pathogenic?

MEGF8 p.Ala2829Val (c.8486C>T) is classified Conflicting classifications of pathogenicity in MEGF8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-26). AlphaMissense: likely benign (0.0815); Very rare (popmax 0.00851%, amr); Associated with MEGF8-related Carpenter syndrome.

What condition is associated with MEGF8 p.Ala2829Val (c.8486C>T)?

MEGF8 p.Ala2829Val (c.8486C>T) is associated with MEGF8-related Carpenter syndrome (ClinVar).

How common is MEGF8 p.Ala2829Val (c.8486C>T) in the general population?

MEGF8 p.Ala2829Val (c.8486C>T) is very rare (popmax 0.00851%, amr) (gnomAD).

What do computational predictors say about MEGF8 p.Ala2829Val (c.8486C>T)?

AlphaMissense predicts likely benign (score 0.0815) — an in-silico prediction, not a clinical call.

MEGF8 p.Ala2829Val

c.8486C>T · rs975858414 · VCV1353530

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0815 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00851%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

MEGF8-related Carpenter syndrome

Computational evidence

Protein change
AlphaMissense	0.0815	likely benign
REVEL	0.014	strongly 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 -0.61
Regional constraint	o/e 0.84	unconstrained · MANE · 51 kb · p 7.6e-23 · regional, not allelic
Overall
CADD	0.487	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 0.00851% Admixed American · 4/47,006 alleles

Filtering AF 0.00288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00174%

Overall 0.000939% 14/1,491,414 alleles · very rare exomes 11/1,339,132 · genomes 3/152,282 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00851%	11,752
African / African-American	0.00551%	18,133
European (non-Finnish)	0.000535%	186,890

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.Ala2829Val
Coding: c.8486C>T
MANE Select: NM_001271938
dbSNP: rs975858414
Type: single nucleotide variant
Location: chr19:42376723 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI <0.01 (gnomAD)
Residue 2829: the 'disordered' region

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.Ala2829= Likely benign ★ 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-ala2829val (accessed [today's date]).

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