Is ADD3 p.Gln63His (c.189A>C) pathogenic?

ADD3 p.Gln63His (c.189A>C) is classified Uncertain significance in ADD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-26). AlphaMissense: likely benign (0.3227); Ultra-rare (popmax 0.0183%, eas).

How common is ADD3 p.Gln63His (c.189A>C) in the general population?

ADD3 p.Gln63His (c.189A>C) is ultra-rare (popmax 0.0183%, eas) (gnomAD).

What do computational predictors say about ADD3 p.Gln63His (c.189A>C)?

AlphaMissense predicts likely benign (score 0.3227) — an in-silico prediction, not a clinical call.

ADD3 p.Gln63His

c.189A>C · rs769661014 · VCV1907415

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3227 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3227	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -4.57	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 2.1	GERP -3.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 33 kb · p 0.53 · regional, not allelic
Overall
CADD	23.0	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 0.0183% East Asian · 8/43,658 alleles

Filtering AF 0.00905% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00656%

Overall 0.000554% 8/1,444,388 alleles · ultra-rare

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.Gln63His
Coding: c.189A>C
MANE Select: NM_016824
dbSNP: rs769661014
Type: single nucleotide variant
Location: chr10:110100842 (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

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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.Arg571His Uncertain significance ★★ ⚠ same type
ADD3 p.Arg645Gln Uncertain significance ★★ ⚠ same type
ADD3 p.Asn312Asp 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-gln63his (accessed [today's date]).

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