Is DOC2A p.Gly44Glu (c.131G>A) pathogenic?

DOC2A p.Gly44Glu (c.131G>A) is classified Uncertain significance in DOC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.097); Ultra-rare (popmax 0.063%, nfe).

How common is DOC2A p.Gly44Glu (c.131G>A) in the general population?

DOC2A p.Gly44Glu (c.131G>A) is ultra-rare (popmax 0.063%, nfe) (gnomAD).

What do computational predictors say about DOC2A p.Gly44Glu (c.131G>A)?

AlphaMissense predicts likely benign (score 0.097) — an in-silico prediction, not a clinical call.

DOC2A p.Gly44Glu

c.131G>A · rs200955492 · VCV2309220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.097 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.063%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.097	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -7.59	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 0.8	GERP 0.084, phastCons 0.24
Regional constraint	o/e 0.86	unconstrained · MANE · 4,033 bp · p 0.00084 · regional, not allelic
Overall
CADD	15.76	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 0.063% European (non-Finnish) · 743/1,179,320 alleles

Filtering AF 0.0592% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0577%

Overall 0.048% 774/1,612,690 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.063%	1,587
Remaining individualsnot grpmax-eligible	0.0176%	5,677
Middle Eastern	0.0165%	6,054
Admixed American	0.0133%	7,497
African / African-American	0.00801%	12,486
Finnishnot grpmax-eligible	0.00629%	15,890
South Asian	0.0011%	91,066

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.Gly44Glu
Coding: c.131G>A
MANE Select: NM_003586
dbSNP: rs200955492
Type: single nucleotide variant
Location: chr16:30010092 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 1 PDB
Residue 44: the 'interaction with unc13d and dynlt1' 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.Ala227Val Uncertain significance ★ ⚠ same type
DOC2A p.Ala228Val Uncertain significance ★ ⚠ same type
DOC2A p.Ala242Val 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-gly44glu (accessed [today's date]).

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