Is DXO p.Arg221His (c.662G>A) pathogenic?

DXO p.Arg221His (c.662G>A) is classified Uncertain significance in DXO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.0883); Very rare (popmax 0.00667%, afr).

How common is DXO p.Arg221His (c.662G>A) in the general population?

DXO p.Arg221His (c.662G>A) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about DXO p.Arg221His (c.662G>A)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

DXO p.Arg221His

c.662G>A · VCV4245691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -9.09	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 3.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,795 bp · p 0.43 · regional, not allelic
Overall
CADD	29.1	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 0.00667% African / African-American · 5/74,976 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000685% 10/1,460,668 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,995
Remaining individualsnot grpmax-eligible	0.0032%	31,248
East Asian	0.00223%	44,864
South Asian	0.0011%	91,072
European (non-Finnish)	8.47e-05%	1,179,988

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: DXO
Protein: p.Arg221His
Coding: c.662G>A
MANE Select: NM_005510
Type: single nucleotide variant
Location: chr6:31970756 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.96

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

Similar variants

DXO p.Arg221Cys Uncertain significance ★ ⚠ same residue
DXO p.Arg221Leu Uncertain significance ★ ⚠ same residue
DXO p.Ala338Thr Uncertain significance ★ ⚠ same type
DXO p.Ala372Thr Uncertain significance ★ ⚠ same type
DXO p.Ala64Asp Uncertain significance ★ ⚠ same type
DXO p.Arg145Gln Uncertain significance ★ ⚠ same type
DXO p.Arg155Gly Uncertain significance ★ ⚠ same type
DXO p.Arg177Gln 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/dxo-p-arg221his (accessed [today's date]).

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