Is DOC2A p.Arg30His (c.89G>A) pathogenic?

DOC2A p.Arg30His (c.89G>A) is classified Uncertain significance in DOC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.1613); Very rare (popmax 0.00533%, afr).

How common is DOC2A p.Arg30His (c.89G>A) in the general population?

DOC2A p.Arg30His (c.89G>A) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about DOC2A p.Arg30His (c.89G>A)?

AlphaMissense predicts likely benign (score 0.1613) — an in-silico prediction, not a clinical call.

DOC2A p.Arg30His

c.89G>A · VCV4661610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1613	likely benign
REVEL	0.427	indeterminate
SaProt	LLR -7.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 4,033 bp · p 0.00084 · regional, not allelic
Overall
CADD	26.2	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 0.00533% African / African-American · 4/75,046 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00204% 33/1,613,800 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,762
South Asian	0.0022%	45,543
European (non-Finnish)	0.00212%	47,195
Admixed American	0.00167%	60,030
Remaining individualsnot grpmax-eligible	0.0016%	62,494

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.Arg30His
Coding: c.89G>A
MANE Select: NM_003586
Type: single nucleotide variant
Location: chr16:30010134 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 1 PDB
Residue 30: the 'interaction with unc13d and dynlt1' 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-arg30his (accessed [today's date]).

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