Is EDA2R p.Pro229Ser (c.685C>T) pathogenic?

EDA2R p.Pro229Ser (c.685C>T) is classified Uncertain significance in EDA2R (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). AlphaMissense: likely benign (0.0941); Very rare (popmax 0.00298%, eas).

How common is EDA2R p.Pro229Ser (c.685C>T) in the general population?

EDA2R p.Pro229Ser (c.685C>T) is very rare (popmax 0.00298%, eas) (gnomAD).

What do computational predictors say about EDA2R p.Pro229Ser (c.685C>T)?

AlphaMissense predicts likely benign (score 0.0941) — an in-silico prediction, not a clinical call.

EDA2R p.Pro229Ser

c.685C>T · rs1928171564 · VCV3087117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00298%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0941	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -3.72	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 5.6	GERP 0.69, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 17 kb · p 0.0014 · regional, not allelic
Overall
CADD	13.9	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 0.00298% East Asian · 1/33,586 alleles

Overall 0.000897% 1/111,506 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: EDA2R
Protein: p.Pro229Ser
Coding: c.685C>T
MANE Select: NM_021783
dbSNP: rs1928171564
Type: single nucleotide variant
Location: chrX:66599693 (GRCh38)
Structure: AlphaFold pLDDT 69.14

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

Similar variants

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
EDA2R p.Cys15Tyr 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-pro229ser (accessed [today's date]).

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