Is DOC2B p.Asp123His (c.367G>C) pathogenic?

DOC2B p.Asp123His (c.367G>C) is classified Uncertain significance in DOC2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely pathogenic (0.8876); Very rare (popmax 0.00426%, amr).

How common is DOC2B p.Asp123His (c.367G>C) in the general population?

DOC2B p.Asp123His (c.367G>C) is very rare (popmax 0.00426%, amr) (gnomAD).

What do computational predictors say about DOC2B p.Asp123His (c.367G>C)?

AlphaMissense predicts likely pathogenic (score 0.8876) — an in-silico prediction, not a clinical call.

DOC2B p.Asp123His

c.367G>C · VCV4014021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00426%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8876	likely pathogenic
REVEL	0.165	moderately benign-leaning
SaProt	LLR -10.06	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	phastCons 1
Overall
CADD	29.6	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 0.00426% Admixed American · 1/23,462 alleles

Filtering AF 0.00213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00185%

Overall 0.00264% 33/1,249,842 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00426%	23,462
European (non-Finnish)	0.00301%	33,228
Remaining individualsnot grpmax-eligible	0.00219%	45,720
African / African-American	0.00156%	64,012

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.Asp123His
Coding: c.367G>C
MANE Select: NM_003585
Type: single nucleotide variant
Location: chr17:181113 (GRCh38)
Gene constraint: LOEUF 1.371 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.21
Residue 123: the 'disordered' region

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.Arg209His 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-asp123his (accessed [today's date]).

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