Is EDA p.Lys375Glu (c.1123A>G) pathogenic?

EDA p.Lys375Glu (c.1123A>G) is classified Conflicting classifications of pathogenicity in EDA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-03-07). AlphaMissense: likely pathogenic (0.6237); Very rare (popmax 0.00176%, afr).

How common is EDA p.Lys375Glu (c.1123A>G) in the general population?

EDA p.Lys375Glu (c.1123A>G) is very rare (popmax 0.00176%, afr) (gnomAD).

What do computational predictors say about EDA p.Lys375Glu (c.1123A>G)?

AlphaMissense predicts likely pathogenic (score 0.6237) — an in-silico prediction, not a clinical call.

EDA p.Lys375Glu

c.1123A>G · rs781394318 · VCV372592

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6237 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6237	likely pathogenic
REVEL	0.591	indeterminate
SaProt	LLR -8.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 4.7, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 419 kb · p 2e-10 · regional, not allelic
Overall
CADD	25.3	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 0.00176% African / African-American · 1/56,927 alleles

Filtering AF 0.000473% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000343%

Overall 0.000911% 10/1,098,144 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00176%	56,927
European (non-Finnish)	0.00101%	99,434

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: EDA
Protein: p.Lys375Glu
Coding: c.1123A>G
MANE Select: NM_001399
dbSNP: rs781394318
Type: single nucleotide variant
Location: chrX:70035556 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 375: a turn; the thd domain

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

Similar variants

EDA p.Lys375Arg Benign ★ same residue
EDA c.526+2T>C Pathogenic/Likely pathogenic ★★ same type
EDA c.526+5G>T Likely pathogenic ★★ same type
EDA c.527-2A>G Pathogenic/Likely pathogenic ★★ same type
EDA c.706+1G>A Pathogenic/Likely pathogenic ★★ same type
EDA c.707-13T>G Pathogenic ★★ same type
EDA c.742-2A>G Pathogenic/Likely pathogenic ★★ same type
EDA c.924+1G>T Likely pathogenic ★★ 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/eda-p-lys375glu (accessed [today's date]).

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