Is ADAD2 p.Arg211His (c.632G>A) pathogenic?

ADAD2 p.Arg211His (c.632G>A) is classified Uncertain significance in ADAD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: ambiguous (0.3792); Ultra-rare (popmax 0.0401%, eas).

How common is ADAD2 p.Arg211His (c.632G>A) in the general population?

ADAD2 p.Arg211His (c.632G>A) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

What do computational predictors say about ADAD2 p.Arg211His (c.632G>A)?

AlphaMissense predicts ambiguous (score 0.3792) — an in-silico prediction, not a clinical call.

ADAD2 p.Arg211His

c.632G>A · VCV3486072

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3792 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3792	ambiguous
REVEL	0.086	moderately benign-leaning
SaProt	LLR -7.83	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP -1.3, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 5,740 bp · p 1.6e-26 · regional, not allelic
Overall
CADD	27.6	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 0.0401% East Asian · 18/44,858 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00167% 27/1,613,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,492
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
South Asian	0.0022%	45,533
European (non-Finnish)	0.000508%	196,662

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.Arg211His
Coding: c.632G>A
MANE Select: NM_001145400
Type: single nucleotide variant
Location: chr16:84195093 (GRCh38)
Gene constraint: LOEUF 1.524 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.35

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-arg211his (accessed [today's date]).

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