Is EDAR p.Ser169Phe (c.506C>T) pathogenic?

EDAR p.Ser169Phe (c.506C>T) is classified Uncertain significance in EDAR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-22). AlphaMissense: likely benign (0.1101); Ultra-rare (popmax 0.0463%, amr); Associated with Inborn genetic diseases.

What condition is associated with EDAR p.Ser169Phe (c.506C>T)?

EDAR p.Ser169Phe (c.506C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EDAR p.Ser169Phe (c.506C>T) in the general population?

EDAR p.Ser169Phe (c.506C>T) is ultra-rare (popmax 0.0463%, amr) (gnomAD).

What do computational predictors say about EDAR p.Ser169Phe (c.506C>T)?

AlphaMissense predicts likely benign (score 0.1101) — an in-silico prediction, not a clinical call.

EDAR p.Ser169Phe

c.506C>T · rs138954516 · VCV2355992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1101 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0463%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1101	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -8.33	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 8.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 34 kb · p 0.0061 · regional, not allelic
Overall
CADD	17.95	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 0.0463% Admixed American · 27/58,266 alleles

Filtering AF 0.0326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.00181% 29/1,599,840 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0463%	2,158
Remaining individualsnot grpmax-eligible	0.00161%	61,970
European (non-Finnish)	8.52e-05%	1,173,658

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.Ser169Phe
Coding: c.506C>T
MANE Select: NM_022336
dbSNP: rs138954516
Type: single nucleotide variant
Location: chr2:108912701 (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-ser169phe (accessed [today's date]).

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