Is DOC2A p.Arg366Trp (c.1096C>T) pathogenic?

DOC2A p.Arg366Trp (c.1096C>T) is classified Uncertain significance in DOC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: likely benign (0.1272); Ultra-rare (popmax 0.0499%, mid).

How common is DOC2A p.Arg366Trp (c.1096C>T) in the general population?

DOC2A p.Arg366Trp (c.1096C>T) is ultra-rare (popmax 0.0499%, mid) (gnomAD).

What do computational predictors say about DOC2A p.Arg366Trp (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.1272) — an in-silico prediction, not a clinical call.

DOC2A p.Arg366Trp

c.1096C>T · rs745345298 · VCV2350293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1272 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0499%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1272	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -7.14	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 2.4	GERP -2, phastCons 0.06
Regional constraint	o/e 0.86	unconstrained · MANE · 4,033 bp · p 0.00084 · regional, not allelic
Overall
CADD	21.0	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 0.0499% Middle Eastern · 3/6,012 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00724%

Overall 0.00292% 47/1,610,268 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0499%	2,004
South Asian	0.0143%	6,988
Admixed American	0.0134%	7,448
Remaining individualsnot grpmax-eligible	0.00962%	10,396
Finnishnot grpmax-eligible	0.00481%	20,793
European (non-Finnish)	0.00119%	84,215

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: DOC2A
Protein: p.Arg366Trp
Coding: c.1096C>T
MANE Select: NM_003586
dbSNP: rs745345298
Type: single nucleotide variant
Location: chr16:30006293 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 1 PDB
Residue 366: the c2 2 domain; the 'interaction with unc13d' region

Full DOC2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOC2A c.715-4G>A Benign ★★ same type
DOC2A p.Gly48Ser Benign ★★ ⚠ same type
DOC2A p.Pro376Leu Benign ★★ ⚠ same type
DOC2A p.Pro392Ala Benign ★★ same type
DOC2A p.Ala125Thr Uncertain significance ★ ⚠ same type
DOC2A p.Ala227Val Uncertain significance ★ ⚠ same type
DOC2A p.Ala228Val Uncertain significance ★ ⚠ same type
DOC2A p.Ala242Val 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/doc2a-p-arg366trp (accessed [today's date]).

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