Is EDAR p.Pro218Ala (c.652C>G) pathogenic?

EDAR p.Pro218Ala (c.652C>G) is classified Uncertain significance in EDAR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.058); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with EDAR p.Pro218Ala (c.652C>G)?

EDAR p.Pro218Ala (c.652C>G) is associated with Inborn genetic diseases (ClinVar).

How common is EDAR p.Pro218Ala (c.652C>G) in the general population?

EDAR p.Pro218Ala (c.652C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about EDAR p.Pro218Ala (c.652C>G)?

AlphaMissense predicts likely benign (score 0.058) — an in-silico prediction, not a clinical call.

EDAR p.Pro218Ala

c.652C>G · VCV4618241

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.058 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.058	likely benign
REVEL	0.374	indeterminate
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 34 kb · p 0.0061 · regional, not allelic
Overall
CADD	21.6	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 0.00133% African / African-American · 1/75,026 alleles

Overall 6.84e-05% 1/1,461,876 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: EDAR
Protein: p.Pro218Ala
Coding: c.652C>G
MANE Select: NM_022336
Type: single nucleotide variant
Location: chr2:108910950 (GRCh38)
Gene constraint: LOEUF 0.927 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.01 · 1 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EDAR p.Ala26Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
EDAR p.Glu35Lys Uncertain significance ★★ ⚠ same condition
EDAR p.Gly321Arg Uncertain significance ★★ ⚠ same condition
EDAR p.Ala174Val Uncertain significance ★ ⚠ same condition
EDAR p.Ala217Ser Uncertain significance ★ ⚠ same condition
EDAR p.Ala260Val Uncertain significance ★ ⚠ same condition
EDAR p.Ala423Thr Uncertain significance ★ ⚠ same condition
EDAR p.Ala99Thr Uncertain significance ★ ⚠ same condition

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/edar-p-pro218ala (accessed [today's date]).

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