Is DOC2B p.Ile12Leu (c.34A>C) pathogenic?

DOC2B p.Ile12Leu (c.34A>C) is classified Uncertain significance in DOC2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.2942); Ultra-rare (popmax 0.0137%, amr).

How common is DOC2B p.Ile12Leu (c.34A>C) in the general population?

DOC2B p.Ile12Leu (c.34A>C) is ultra-rare (popmax 0.0137%, amr) (gnomAD).

What do computational predictors say about DOC2B p.Ile12Leu (c.34A>C)?

AlphaMissense predicts likely benign (score 0.2942) — an in-silico prediction, not a clinical call.

DOC2B p.Ile12Leu

c.34A>C · rs931535608 · VCV2515077

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2942 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2942	likely benign
REVEL	0.408	indeterminate
SaProt	LLR -5.35	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 6.9	phastCons 1
Overall
CADD	23.5	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 0.0137% Admixed American · 4/29,208 alleles

Filtering AF 0.00459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.000432% 5/1,156,324 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0137%	7,302
European (non-Finnish)	0.000108%	926,535

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.Ile12Leu
Coding: c.34A>C
MANE Select: NM_003585
dbSNP: rs931535608
Type: single nucleotide variant
Location: chr17:181446 (GRCh38)
Gene constraint: LOEUF 1.371 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.21
Residue 12: the 'mediates interaction with dynlt1' region; the 'negatively regulates targeting to plasma membrane' region

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

Similar variants

DOC2B p.Ile12Asn 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.Arg186Cys Uncertain significance ★ same type
DOC2B p.Arg186His 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-ile12leu (accessed [today's date]).

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