Is DOC2A p.Ser163Arg (c.489C>A) pathogenic?

DOC2A p.Ser163Arg (c.489C>A) is classified Uncertain significance in DOC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-17). AlphaMissense: likely benign (0.2162); Ultra-rare (popmax 0.0593%, sas).

How common is DOC2A p.Ser163Arg (c.489C>A) in the general population?

DOC2A p.Ser163Arg (c.489C>A) is ultra-rare (popmax 0.0593%, sas) (gnomAD).

What do computational predictors say about DOC2A p.Ser163Arg (c.489C>A)?

AlphaMissense predicts likely benign (score 0.2162) — an in-silico prediction, not a clinical call.

DOC2A p.Ser163Arg

c.489C>A · rs200874282 · VCV3084876

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2162 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0593%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2162	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -8.40	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 -4.2	GERP -3.5
Regional constraint	o/e 0.86	unconstrained · MANE · 4,033 bp · p 0.00084 · regional, not allelic
Overall
CADD	0.003	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 0.0593% South Asian · 54/91,060 alleles

Filtering AF 0.0466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0421%

Overall 0.00589% 95/1,613,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0593%	1,686
Middle Eastern	0.0503%	1,989
Remaining individualsnot grpmax-eligible	0.0128%	7,811
African / African-American	0.00267%	37,512
European (non-Finnish)	0.00229%	43,703
Admixed American	0.00167%	60,020

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.Ser163Arg
Coding: c.489C>A
MANE Select: NM_003586
dbSNP: rs200874282
Type: single nucleotide variant
Location: chr16:30009034 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 1 PDB
Residue 163: the c2 1 domain

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-ser163arg (accessed [today's date]).

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