Is EDAR p.Cys148Ser (c.442T>A) pathogenic?

EDAR p.Cys148Ser (c.442T>A) is classified Likely pathogenic in EDAR (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-01). AlphaMissense: likely pathogenic (0.9918); Very rare (popmax 0.00288%, nfe); Associated with ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive.

What condition is associated with EDAR p.Cys148Ser (c.442T>A)?

EDAR p.Cys148Ser (c.442T>A) is associated with ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive (ClinVar).

How common is EDAR p.Cys148Ser (c.442T>A) in the general population?

EDAR p.Cys148Ser (c.442T>A) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about EDAR p.Cys148Ser (c.442T>A)?

AlphaMissense predicts likely pathogenic (score 0.9918) — an in-silico prediction, not a clinical call.

EDAR p.Cys148Ser

c.442T>A · VCV4974488

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9918 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9918	likely pathogenic ✓ concordant with ClinVar · top 6% in EDAR
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -14.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 34 kb · p 0.0061 · regional, not allelic
Overall
CADD	29.5	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 0.00288% European (non-Finnish) · 34/1,179,908 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.0026% 38/1,461,736 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,628
European (non-Finnish)grpmax	0.00288%	34,703

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys148Ser
Coding: c.442T>A
MANE Select: NM_022336
Type: single nucleotide variant
Location: chr2:108923368 (GRCh38)
Gene constraint: LOEUF 0.927 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.01 · 1 PDB
Residue 148: a disulfide bond; a UniProt-annotated variant site (in ectd10b)

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

Disease context

ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EDAR p.Cys148Arg Likely pathogenic ★★ same residue
EDAR c.730+1G>T Pathogenic ★★ same condition
EDAR p.Ala26Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
EDAR p.Arg89His Pathogenic/Likely pathogenic ★★ ⚠ same condition
EDAR p.Arg98Trp Pathogenic/Likely pathogenic ★★ same condition
EDAR p.Gly382Ser Pathogenic ★★ ⚠ same condition
EDAR p.Ala291Thr Uncertain significance ★★ ⚠ same condition
EDAR c.1024+44C>T 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/edar-p-cys148ser (accessed [today's date]).

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