Is DOC2A p.Ala227Val (c.680C>T) pathogenic?

DOC2A p.Ala227Val (c.680C>T) is classified Uncertain significance in DOC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). AlphaMissense: likely benign (0.1277); Ultra-rare (popmax 0.0467%, afr).

How common is DOC2A p.Ala227Val (c.680C>T) in the general population?

DOC2A p.Ala227Val (c.680C>T) is ultra-rare (popmax 0.0467%, afr) (gnomAD).

What do computational predictors say about DOC2A p.Ala227Val (c.680C>T)?

AlphaMissense predicts likely benign (score 0.1277) — an in-silico prediction, not a clinical call.

DOC2A p.Ala227Val

c.680C>T · VCV3841849

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1277 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1277	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -7.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 4,033 bp · p 0.00084 · regional, not allelic
Overall
CADD	21.4	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 0.0467% African / African-American · 35/75,022 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.00273% 44/1,614,026 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0467%	2,143
Admixed American	0.00333%	30,010
South Asian	0.0022%	45,539
European (non-Finnish)	0.000424%	235,995

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: DOC2A
Protein: p.Ala227Val
Coding: c.680C>T
MANE Select: NM_003586
Type: single nucleotide variant
Location: chr16:30007065 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 1 PDB
Residue 227: the 'interaction with unc13d' region

Full DOC2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOC2A c.715-4G>A Benign ★★ same type
DOC2A p.Gly48Ser Benign ★★ ⚠ same type
DOC2A p.Pro376Leu Benign ★★ ⚠ same type
DOC2A p.Pro392Ala Benign ★★ same type
DOC2A p.Ala125Thr Uncertain significance ★ ⚠ same type
DOC2A p.Ala228Val Uncertain significance ★ ⚠ same type
DOC2A p.Ala242Val Uncertain significance ★ ⚠ same type
DOC2A p.Ala332Thr 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/doc2a-p-ala227val (accessed [today's date]).

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