Is DOC2B p.Arg209His (c.626G>A) pathogenic?

DOC2B p.Arg209His (c.626G>A) is classified Uncertain significance in DOC2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-14). AlphaMissense: ambiguous (0.3779); Ultra-rare (popmax 0.0389%, nfe).

How common is DOC2B p.Arg209His (c.626G>A) in the general population?

DOC2B p.Arg209His (c.626G>A) is ultra-rare (popmax 0.0389%, nfe) (gnomAD).

What do computational predictors say about DOC2B p.Arg209His (c.626G>A)?

AlphaMissense predicts ambiguous (score 0.3779) — an in-silico prediction, not a clinical call.

DOC2B p.Arg209His

c.626G>A · rs369343321 · VCV3084887

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3779 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0389%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3779	ambiguous
REVEL	0.057	moderately benign-leaning
SaProt	LLR -10.07	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	phastCons 0.99
Overall
CADD	22.6	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 0.0389% European (non-Finnish) · 446/1,146,226 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0347%

Overall 0.0302% 469/1,550,760 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0389%	2,570
African / African-American	0.0151%	6,639
Remaining individualsnot grpmax-eligible	0.0133%	7,511
East Asian	0.00489%	20,457
South Asian	0.00238%	42,022

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.Arg209His
Coding: c.626G>A
MANE Select: NM_003585
dbSNP: rs369343321
Type: single nucleotide variant
Location: chr17:162093 (GRCh38)
Gene constraint: LOEUF 1.371 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.21
Residue 209: the c2 1 domain; a UniProt-annotated variant site (in a patient with amyotrophic lateral sclerosis)

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

Similar variants

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.Arg186Cys Uncertain significance ★ same type
DOC2B p.Arg186His 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-arg209his (accessed [today's date]).

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