Is EDEM2 p.Ser206Arg (c.616A>C) pathogenic?

EDEM2 p.Ser206Arg (c.616A>C) is classified Uncertain significance in EDEM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.9915); Absent from gnomAD v4.1.

How common is EDEM2 p.Ser206Arg (c.616A>C) in the general population?

EDEM2 p.Ser206Arg (c.616A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EDEM2 p.Ser206Arg (c.616A>C)?

AlphaMissense predicts likely pathogenic (score 0.9915) — an in-silico prediction, not a clinical call.

EDEM2 p.Ser206Arg

c.616A>C · VCV4663058

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9915 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9915	likely pathogenic · top 10% in EDEM2
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -15.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 32 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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: EDEM2
Protein: p.Ser206Arg
Coding: c.616A>C
MANE Select: NM_018217
Type: single nucleotide variant
Location: chr20:35134824 (GRCh38)
Gene constraint: LOEUF 0.749 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.61

Full EDEM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDEM2 p.Ala251Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Ala484Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Ala529Glu Uncertain significance ★ ⚠ same type
EDEM2 p.Ala81Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Arg219Thr Uncertain significance ★ ⚠ same type
EDEM2 p.Arg224Cys Uncertain significance ★ ⚠ same type
EDEM2 p.Arg224His Uncertain significance ★ ⚠ same type
EDEM2 p.Arg229Gln Uncertain significance ★ ⚠ same type

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/edem2-p-ser206arg (accessed [today's date]).

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