Is EDDM3B p.Cys80Arg (c.238T>C) pathogenic?

EDDM3B p.Cys80Arg (c.238T>C) is classified Uncertain significance in EDDM3B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). AlphaMissense: likely pathogenic (0.9623); Very rare (popmax 0.00223%, eas).

How common is EDDM3B p.Cys80Arg (c.238T>C) in the general population?

EDDM3B p.Cys80Arg (c.238T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about EDDM3B p.Cys80Arg (c.238T>C)?

AlphaMissense predicts likely pathogenic (score 0.9623) — an in-silico prediction, not a clinical call.

EDDM3B p.Cys80Arg

c.238T>C · VCV3274481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9623	likely pathogenic · top 2% in EDDM3B
REVEL	0.65	pathogenic-leaning
SaProt	LLR -17.64	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 5.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 440 bp · p 0.42 · regional, not allelic
Overall
CADD	22.5	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

Grpmax group 0.00223% East Asian · 1/44,882 alleles

Overall 6.84e-05% 1/1,461,888 alleles · very rare

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: EDDM3B
Protein: p.Cys80Arg
Coding: c.238T>C
MANE Select: NM_022360
Type: single nucleotide variant
Location: chr14:20770388 (GRCh38)
Gene constraint: LOEUF 1.883 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 90.55

Full EDDM3B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDDM3B p.Arg88His Uncertain significance ★ ⚠ same type
EDDM3B p.Arg90Leu Uncertain significance ★ ⚠ same type
EDDM3B p.Asn109Lys Uncertain significance ★ ⚠ same type
EDDM3B p.Asp130Gly Uncertain significance ★ ⚠ same type
EDDM3B p.Asp62Tyr Uncertain significance ★ ⚠ same type
EDDM3B p.Glu108Lys Uncertain significance ★ ⚠ same type
EDDM3B p.Glu124Ala Uncertain significance ★ ⚠ same type
EDDM3B p.Glu27Lys 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/eddm3b-p-cys80arg (accessed [today's date]).

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