Is DOC2B p.Pro45Ser (c.133C>T) pathogenic?

DOC2B p.Pro45Ser (c.133C>T) is classified Uncertain significance in DOC2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.115); Very rare (popmax 0.00959%, amr).

How common is DOC2B p.Pro45Ser (c.133C>T) in the general population?

DOC2B p.Pro45Ser (c.133C>T) is very rare (popmax 0.00959%, amr) (gnomAD).

What do computational predictors say about DOC2B p.Pro45Ser (c.133C>T)?

AlphaMissense predicts likely benign (score 0.115) — an in-silico prediction, not a clinical call.

DOC2B p.Pro45Ser

c.133C>T · rs1471949149 · VCV3084880

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.115 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00959%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.115	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	phastCons 1
Overall
CADD	20.8	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 0.00959% Admixed American · 2/20,864 alleles

Filtering AF 0.00168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000692%

Overall 0.000354% 4/1,130,278 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00959%	10,432
Finnishnot grpmax-eligible	0.00399%	25,092
European (non-Finnish)	0.000108%	923,344

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.Pro45Ser
Coding: c.133C>T
MANE Select: NM_003585
dbSNP: rs1471949149
Type: single nucleotide variant
Location: chr17:181347 (GRCh38)
Gene constraint: LOEUF 1.371 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.21
Residue 45: the 'mediates interaction with dynlt1' region; 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-pro45ser (accessed [today's date]).

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