Is ADAD2 p.Ala124Glu (c.371C>A) pathogenic?

ADAD2 p.Ala124Glu (c.371C>A) is classified Uncertain significance in ADAD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely pathogenic (0.8172); Very rare (popmax 0.00923%, nfe).

How common is ADAD2 p.Ala124Glu (c.371C>A) in the general population?

ADAD2 p.Ala124Glu (c.371C>A) is very rare (popmax 0.00923%, nfe) (gnomAD).

What do computational predictors say about ADAD2 p.Ala124Glu (c.371C>A)?

AlphaMissense predicts likely pathogenic (score 0.8172) — an in-silico prediction, not a clinical call.

ADAD2 p.Ala124Glu

c.371C>A · rs1014702043 · VCV3143649

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8172 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00923%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8172	likely pathogenic · top 9% in ADAD2
REVEL	0.276	benign-leaning
SaProt	LLR -11.28	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -1.9, phastCons 0.12
Regional constraint	o/e 1.38	unconstrained · MANE · 5,740 bp · p 1.6e-26 · regional, not allelic
Overall
CADD	19.88	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 0.00923% European (non-Finnish) · 106/1,148,132 alleles

Filtering AF 0.00778% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00726%

Overall 0.00696% 108/1,552,028 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00923%	10,831
Remaining individualsnot grpmax-eligible	0.00333%	30,072

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: ADAD2
Protein: p.Ala124Glu
Coding: c.371C>A
MANE Select: NM_001145400
dbSNP: rs1014702043
Type: single nucleotide variant
Location: chr16:84191601 (GRCh38)
Gene constraint: LOEUF 1.524 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.35
Residue 124: the drbm domain

Full ADAD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAD2 p.Arg180Gln Likely benign ★★ ⚠ same type
ADAD2 c.419-254A>G Uncertain significance ★ same type
ADAD2 c.419-262T>C Uncertain significance ★ same type
ADAD2 c.419-274C>T Uncertain significance ★ same type
ADAD2 c.419-334G>A Uncertain significance ★ same type
ADAD2 c.419-334G>T Uncertain significance ★ same type
ADAD2 c.419-376A>C Uncertain significance ★ same type
ADAD2 c.419-409G>A Uncertain significance ★ 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/adad2-p-ala124glu (accessed [today's date]).

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