Is ADAD2 p.Val460Ile (c.1378G>A) pathogenic?

ADAD2 p.Val460Ile (c.1378G>A) is classified Uncertain significance in ADAD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-13). AlphaMissense: likely benign (0.0865); Ultra-rare (popmax 0.0147%, afr).

How common is ADAD2 p.Val460Ile (c.1378G>A) in the general population?

ADAD2 p.Val460Ile (c.1378G>A) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about ADAD2 p.Val460Ile (c.1378G>A)?

AlphaMissense predicts likely benign (score 0.0865) — an in-silico prediction, not a clinical call.

ADAD2 p.Val460Ile

c.1378G>A · rs369743783 · VCV2387457

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0865 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0865	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -7.84	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 -0.032	GERP -2.8
Regional constraint	o/e 1.38	unconstrained · MANE · 5,740 bp · p 1.6e-26 · regional, not allelic
Overall
CADD	8.264	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 0.0147% African / African-American · 11/74,894 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00459% 74/1,611,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,809
Finnishnot grpmax-eligible	0.00979%	10,215
Remaining individualsnot grpmax-eligible	0.00801%	12,491
South Asian	0.00769%	13,011
European (non-Finnish)	0.00373%	26,816
Admixed American	0.00167%	60,000

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.Val460Ile
Coding: c.1378G>A
MANE Select: NM_001145400
dbSNP: rs369743783
Type: single nucleotide variant
Location: chr16:84196222 (GRCh38)
Gene constraint: LOEUF 1.524 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.35
Residue 460: the a to i editase domain; a UniProt-annotated variant site (found in a patient with non-obstructive azoospermia; uncertain significance)

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-val460ile (accessed [today's date]).

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