Is EDDM3A p.Arg78Cys (c.232C>T) pathogenic?

EDDM3A p.Arg78Cys (c.232C>T) is classified Uncertain significance in EDDM3A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely benign (0.2264); Ultra-rare (popmax 0.0588%, afr).

How common is EDDM3A p.Arg78Cys (c.232C>T) in the general population?

EDDM3A p.Arg78Cys (c.232C>T) is ultra-rare (popmax 0.0588%, afr) (gnomAD).

What do computational predictors say about EDDM3A p.Arg78Cys (c.232C>T)?

AlphaMissense predicts likely benign (score 0.2264) — an in-silico prediction, not a clinical call.

EDDM3A p.Arg78Cys

c.232C>T · rs755249699 · VCV2240965

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2264 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0588%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2264	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -9.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.3	GERP -0.85
Regional constraint	o/e 1.12	unconstrained · MANE · 440 bp · p 0.1 · regional, not allelic
Overall
CADD	17.76	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0588% African / African-American · 44/74,860 alleles

Filtering AF 0.0449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0401%

Overall 0.00341% 55/1,613,904 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0588%	1,701
South Asian	0.00549%	18,216
Remaining individualsnot grpmax-eligible	0.0048%	20,828
Admixed American	0.00167%	59,998
European (non-Finnish)	0.000169%	589,998

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: EDDM3A
Protein: p.Arg78Cys
Coding: c.232C>T
MANE Select: NM_006683
dbSNP: rs755249699
Type: single nucleotide variant
Location: chr14:20747812 (GRCh38)
Gene constraint: LOEUF 1.943 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 91.64

Full EDDM3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDDM3A p.Arg118Lys Uncertain significance ★ ⚠ same type
EDDM3A p.Arg43Gln Uncertain significance ★ ⚠ same type
EDDM3A p.Asn26Ser Uncertain significance ★ ⚠ same type
EDDM3A p.Asp130Gly Uncertain significance ★ ⚠ same type
EDDM3A p.Cys127Trp Uncertain significance ★ ⚠ same type
EDDM3A p.Cys22Trp Uncertain significance ★ ⚠ same type
EDDM3A p.Cys22Tyr Uncertain significance ★ ⚠ same type
EDDM3A p.Cys80Tyr 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/eddm3a-p-arg78cys (accessed [today's date]).

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