Is DOC2B p.Ala58Ser (c.172G>T) pathogenic?

DOC2B p.Ala58Ser (c.172G>T) is classified Uncertain significance in DOC2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-04). AlphaMissense: likely benign (0.08); Ultra-rare (popmax 0.0113%, afr).

How common is DOC2B p.Ala58Ser (c.172G>T) in the general population?

DOC2B p.Ala58Ser (c.172G>T) is ultra-rare (popmax 0.0113%, afr) (gnomAD).

What do computational predictors say about DOC2B p.Ala58Ser (c.172G>T)?

AlphaMissense predicts likely benign (score 0.08) — an in-silico prediction, not a clinical call.

DOC2B p.Ala58Ser

c.172G>T · VCV4014020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.08 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.08	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -7.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	phastCons 0.99
Overall
CADD	13.62	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 0.0113% African / African-American · 7/61,730 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.0011% 13/1,177,374 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0113%	8,819
Admixed American	0.00923%	10,829
Remaining individualsnot grpmax-eligible	0.0072%	13,889
South Asian	0.00417%	23,976

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.Ala58Ser
Coding: c.172G>T
MANE Select: NM_003585
Type: single nucleotide variant
Location: chr17:181308 (GRCh38)
Gene constraint: LOEUF 1.371 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.21
Residue 58: 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.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
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-ala58ser (accessed [today's date]).

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