Is DOC2A p.Arg8Ser (c.22C>A) pathogenic?

DOC2A p.Arg8Ser (c.22C>A) is classified Uncertain significance in DOC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-24). AlphaMissense: ambiguous (0.4201); Absent from gnomAD v4.1.

How common is DOC2A p.Arg8Ser (c.22C>A) in the general population?

DOC2A p.Arg8Ser (c.22C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DOC2A p.Arg8Ser (c.22C>A)?

AlphaMissense predicts ambiguous (score 0.4201) — an in-silico prediction, not a clinical call.

DOC2A p.Arg8Ser

c.22C>A · VCV3273273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4201 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4201	ambiguous
REVEL	0.446	indeterminate
SaProt	LLR -5.71	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 4,033 bp · p 0.00084 · regional, not allelic
Overall
CADD	24.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DOC2A
Protein: p.Arg8Ser
Coding: c.22C>A
MANE Select: NM_003586
Type: single nucleotide variant
Location: chr16:30010201 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 1 PDB
Residue 8: the 'interaction with unc13d and dynlt1' region

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

Similar variants

DOC2A p.Arg8Gly Uncertain significance ★ ⚠ same residue
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

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-arg8ser (accessed [today's date]).

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