Is ADD3 p.Arg571His (c.1712G>A) pathogenic?

ADD3 p.Arg571His (c.1712G>A) is classified Uncertain significance in ADD3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-24). AlphaMissense: likely benign (0.1041); Ultra-rare (popmax 0.0813%, afr).

How common is ADD3 p.Arg571His (c.1712G>A) in the general population?

ADD3 p.Arg571His (c.1712G>A) is ultra-rare (popmax 0.0813%, afr) (gnomAD).

What do computational predictors say about ADD3 p.Arg571His (c.1712G>A)?

AlphaMissense predicts likely benign (score 0.1041) — an in-silico prediction, not a clinical call.

ADD3 p.Arg571His

c.1712G>A · rs141186367 · VCV1399000

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1041 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0813%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1041	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -12.34	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 33 kb · p 0.53 · regional, not allelic
Overall
CADD	27.4	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 0.0813% African / African-American · 61/75,028 alleles

Filtering AF 0.0649% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.059%

Overall 0.00973% 157/1,613,776 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0813%	1,230
Middle Eastern	0.0165%	6,060
Admixed American	0.0133%	7,499
European (non-Finnish)	0.00712%	14,045
Remaining individualsnot grpmax-eligible	0.0048%	20,831

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: ADD3
Protein: p.Arg571His
Coding: c.1712G>A
MANE Select: NM_016824
dbSNP: rs141186367
Type: single nucleotide variant
Location: chr10:110130466 (GRCh38)
Gene constraint: LOEUF 0.395 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.83

Full ADD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADD3 p.Gly367Asp Pathogenic/Likely pathogenic ★★ same type
ADD3 c.1733-1G>A Uncertain significance ★★ same type
ADD3 p.Ala588Gly Uncertain significance ★★ ⚠ same type
ADD3 p.Arg27Cys Uncertain significance ★★ ⚠ same type
ADD3 p.Arg46Gln Uncertain significance ★★ ⚠ same type
ADD3 p.Arg645Gln Uncertain significance ★★ ⚠ same type
ADD3 p.Asn312Asp Uncertain significance ★★ ⚠ same type
ADD3 p.Asn332Ser 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/add3-p-arg571his (accessed [today's date]).

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