Is DOC2B p.Arg223Gln (c.668G>A) pathogenic?

DOC2B p.Arg223Gln (c.668G>A) is classified Uncertain significance in DOC2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-26). AlphaMissense: ambiguous (0.4338); Very rare (popmax 0.00274%, afr).

How common is DOC2B p.Arg223Gln (c.668G>A) in the general population?

DOC2B p.Arg223Gln (c.668G>A) is very rare (popmax 0.00274%, afr) (gnomAD).

What do computational predictors say about DOC2B p.Arg223Gln (c.668G>A)?

AlphaMissense predicts ambiguous (score 0.4338) — an in-silico prediction, not a clinical call.

DOC2B p.Arg223Gln

c.668G>A · rs977032944 · VCV3084888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4338 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00274%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4338	ambiguous
REVEL	0.043	moderately benign-leaning
SaProt	LLR -8.26	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 7.7	phastCons 1
Overall
CADD	25.1	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 0.00274% African / African-American · 2/73,048 alleles

Filtering AF 0.000454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.000902% 14/1,551,594 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00333%	30,048
African / African-Americangrpmax	0.00274%	36,524
South Asian	0.00238%	42,031
Admixed American	0.00196%	50,996
European (non-Finnish)	0.00061%	163,857

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DOC2B
Protein: p.Arg223Gln
Coding: c.668G>A
MANE Select: NM_003585
dbSNP: rs977032944
Type: single nucleotide variant
Location: chr17:161512 (GRCh38)
Gene constraint: LOEUF 1.371 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.21
Residue 223: the c2 1 domain

Full DOC2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOC2B p.Ala103Thr Uncertain significance ★ ⚠ same type
DOC2B p.Ala295Thr Uncertain significance ★ ⚠ same type
DOC2B p.Ala54Glu Uncertain significance ★ ⚠ same type
DOC2B p.Ala58Ser Uncertain significance ★ ⚠ same type
DOC2B p.Ala63Thr Uncertain significance ★ ⚠ same type
DOC2B p.Arg186Cys Uncertain significance ★ ⚠ same type
DOC2B p.Arg186His Uncertain significance ★ ⚠ same type
DOC2B p.Arg209His 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/doc2b-p-arg223gln (accessed [today's date]).

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