Is EDARADD p.Ser149Phe (c.446C>T) pathogenic?

EDARADD p.Ser149Phe (c.446C>T) is classified Uncertain significance in EDARADD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-19). AlphaMissense: likely pathogenic (0.5775); Absent from gnomAD v4.1; Associated with ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant.

What condition is associated with EDARADD p.Ser149Phe (c.446C>T)?

EDARADD p.Ser149Phe (c.446C>T) is associated with ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant, ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive (ClinVar).

How common is EDARADD p.Ser149Phe (c.446C>T) in the general population?

EDARADD p.Ser149Phe (c.446C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EDARADD p.Ser149Phe (c.446C>T)?

AlphaMissense predicts likely pathogenic (score 0.5775) — an in-silico prediction, not a clinical call.

EDARADD p.Ser149Phe

c.446C>T · rs2103042663 · VCV1439044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5775 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.5775	likely pathogenic
REVEL	0.361	indeterminate
SaProt	LLR -12.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.76, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 88 kb · p 0.0061 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EDARADD
Protein: p.Ser149Phe
Coding: c.446C>T
MANE Select: NM_145861
dbSNP: rs2103042663
Type: single nucleotide variant
Location: chr1:236482447 (GRCh38)
Gene constraint: LOEUF 0.991 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.81
Residue 149: the death domain

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

Disease context

ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive

Similar variants

EDARADD p.Arg66Ter Pathogenic ★★ same condition
EDARADD p.Arg170Gln Uncertain significance ★★ ⚠ same condition
EDARADD p.Asp120His Uncertain significance ★★ ⚠ same condition
EDARADD p.Gln8Glu Uncertain significance ★★ ⚠ same condition
EDARADD p.Gly74Arg Uncertain significance ★★ ⚠ same condition
EDARADD c.120+7G>A Benign ★★ same condition
EDARADD c.121-19C>T Benign ★★ same condition
EDARADD c.161-13T>C Benign/Likely benign ★★ 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/edaradd-p-ser149phe (accessed [today's date]).

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