Is DOC2B p.Arg186Cys (c.556C>T) pathogenic?

DOC2B p.Arg186Cys (c.556C>T) is classified Uncertain significance in DOC2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.5025); Very rare (popmax 0.00548%, afr).

How common is DOC2B p.Arg186Cys (c.556C>T) in the general population?

DOC2B p.Arg186Cys (c.556C>T) is very rare (popmax 0.00548%, afr) (gnomAD).

What do computational predictors say about DOC2B p.Arg186Cys (c.556C>T)?

AlphaMissense predicts ambiguous (score 0.5025) — an in-silico prediction, not a clinical call.

DOC2B p.Arg186Cys

c.556C>T · VCV4243735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5025 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00548%, afr)

Computational evidence

Protein change
AlphaMissense	0.5025	ambiguous
REVEL	0.435	indeterminate
SaProt	LLR -11.53	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	phastCons 1
Overall
CADD	29.7	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 0.00548% African / African-American · 4/73,022 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00106%

Overall 0.00142% 22/1,551,696 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00548%	18,256
European (non-Finnish)	0.00148%	67,468
South Asian	0.00119%	84,054

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.Arg186Cys
Coding: c.556C>T
MANE Select: NM_003585
Type: single nucleotide variant
Location: chr17:162163 (GRCh38)
Gene constraint: LOEUF 1.371 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.21
Residue 186: the c2 1 domain

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

Similar variants

DOC2B p.Arg186His Uncertain significance ★ ⚠ same residue
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.Arg209His Uncertain significance ★ ⚠ same type
DOC2B p.Arg223Gln 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-arg186cys (accessed [today's date]).

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