Is MEGF8 p.Pro355Ser (c.1063C>T) pathogenic?

MEGF8 p.Pro355Ser (c.1063C>T) is classified Uncertain significance in MEGF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-18). AlphaMissense: likely benign (0.0757); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MEGF8 p.Pro355Ser (c.1063C>T)?

MEGF8 p.Pro355Ser (c.1063C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MEGF8 p.Pro355Ser (c.1063C>T) in the general population?

MEGF8 p.Pro355Ser (c.1063C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MEGF8 p.Pro355Ser (c.1063C>T)?

AlphaMissense predicts likely benign (score 0.0757) — an in-silico prediction, not a clinical call.

MEGF8 p.Pro355Ser

c.1063C>T · rs2039125091 · VCV2290064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0757 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0757	likely benign
REVEL	0.109	moderately 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 7.7	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 51 kb · p 7.6e-23 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MEGF8
Protein: p.Pro355Ser
Coding: c.1063C>T
MANE Select: NM_001271938
dbSNP: rs2039125091
Type: single nucleotide variant
Location: chr19:42336165 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MEGF8 p.Pro355Leu Likely benign ★ same residue
MEGF8 p.Ala1554Val Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala1572Thr Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala176Gly Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala2349Gly Uncertain significance ★★ same condition
MEGF8 p.Ala234Thr Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala2531Val Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala264Thr 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-pro355ser (accessed [today's date]).

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