Is ADAD2 p.Pro144Arg (c.431C>G) pathogenic?

ADAD2 p.Pro144Arg (c.431C>G) is classified Uncertain significance in ADAD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-14). AlphaMissense: likely benign (0.1101); Very rare (popmax 0.00534%, afr).

How common is ADAD2 p.Pro144Arg (c.431C>G) in the general population?

ADAD2 p.Pro144Arg (c.431C>G) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about ADAD2 p.Pro144Arg (c.431C>G)?

AlphaMissense predicts likely benign (score 0.1101) — an in-silico prediction, not a clinical call.

ADAD2 p.Pro144Arg

c.431C>G · VCV3827547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1101	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -7.18	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	GERP -0.69
Regional constraint	o/e 1.38	unconstrained · MANE · 5,740 bp · p 1.6e-26 · regional, not allelic
Overall
CADD	14.81	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 0.00534% African / African-American · 4/74,864 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000311% 5/1,606,142 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,716
Admixed American	0.00167%	59,892

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.Pro144Arg
Coding: c.431C>G
MANE Select: NM_001145400
Type: single nucleotide variant
Location: chr16:84194454 (GRCh38)
Gene constraint: LOEUF 1.524 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.35
Residue 144: 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-pro144arg (accessed [today's date]).

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