Is EDA2R p.Pro45Leu (c.134C>T) pathogenic?

EDA2R p.Pro45Leu (c.134C>T) is classified Uncertain significance in EDA2R (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.1402); Very rare (popmax 0.00298%, eas).

How common is EDA2R p.Pro45Leu (c.134C>T) in the general population?

EDA2R p.Pro45Leu (c.134C>T) is very rare (popmax 0.00298%, eas) (gnomAD).

What do computational predictors say about EDA2R p.Pro45Leu (c.134C>T)?

AlphaMissense predicts likely benign (score 0.1402) — an in-silico prediction, not a clinical call.

EDA2R p.Pro45Leu

c.134C>T · rs757586946 · VCV3087114

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1402 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00298%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1402	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -10.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -3.1, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 17 kb · p 0.0014 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00298% East Asian · 1/33,608 alleles

Filtering AF 0.000385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.000745% 9/1,207,947 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00298%	33,608
European (non-Finnish)	0.000895%	111,792

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: EDA2R
Protein: p.Pro45Leu
Coding: c.134C>T
MANE Select: NM_021783
dbSNP: rs757586946
Type: single nucleotide variant
Location: chrX:66605180 (GRCh38)
Structure: AlphaFold pLDDT 69.14
Residue 45: a disulfide bond

Full EDA2R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDA2R p.Pro45= Likely benign ★ same residue
EDA2R p.Leu27= Benign ★★ same type
EDA2R p.Pro112Ser Likely benign ★★ ⚠ same type
EDA2R p.Tyr8His Benign ★★ same type
EDA2R p.Ala119Val Uncertain significance ★ ⚠ same type
EDA2R p.Arg14Gln Uncertain significance ★ ⚠ same type
EDA2R p.Arg47Cys Uncertain significance ★ ⚠ same type
EDA2R p.Arg95Cys 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/eda2r-p-pro45leu (accessed [today's date]).

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