Is ADAD2 p.Gln40Pro (c.119A>C) pathogenic?

ADAD2 p.Gln40Pro (c.119A>C) is classified Uncertain significance in ADAD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely benign (0.0506); Rare (popmax 0.338%, afr).

How common is ADAD2 p.Gln40Pro (c.119A>C) in the general population?

ADAD2 p.Gln40Pro (c.119A>C) is rare (popmax 0.338%, afr) (gnomAD).

What do computational predictors say about ADAD2 p.Gln40Pro (c.119A>C)?

AlphaMissense predicts likely benign (score 0.0506) — an in-silico prediction, not a clinical call.

ADAD2 p.Gln40Pro

c.119A>C · VCV4224169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0506 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.338%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0506	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -3.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -3.6
Regional constraint	o/e 1.38	unconstrained · MANE · 5,740 bp · p 1.6e-26 · regional, not allelic
Overall
CADD	0.108	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 0.338% African / African-American · 247/73,114 alleles

Filtering AF 0.303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.29%

Overall 0.0199% 312/1,570,424 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.338%	296
Remaining individualsnot grpmax-eligible	0.0348%	2,872
Admixed American	0.0225%	4,438
Middle Eastern	0.0193%	5,192
European (non-Finnish)	0.00258%	38,692
South Asian	0.00113%	88,622

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.Gln40Pro
Coding: c.119A>C
MANE Select: NM_001145400
Type: single nucleotide variant
Location: chr16:84191349 (GRCh38)
Gene constraint: LOEUF 1.524 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.35
Residue 40: the 'disordered' region

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-gln40pro (accessed [today's date]).

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