Is DOC2A p.Gly48Ser (c.142G>A) pathogenic?

DOC2A p.Gly48Ser (c.142G>A) is classified Benign in DOC2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0912); Common (popmax 44%, sas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about DOC2A p.Gly48Ser (c.142G>A)?

AlphaMissense predicts likely benign (score 0.0912) — an in-silico prediction, not a clinical call.

DOC2A p.Gly48Ser

Q: How common is DOC2A p.Gly48Ser (c.142G>A) in the general population?

DOC2A p.Gly48Ser (c.142G>A) is common (popmax 44%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.142G>A · rs1140239 · VCV769898

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0912 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 44%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0912	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -9.05	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 0.94	GERP -0.7, phastCons 0.28
Regional constraint	o/e 0.86	unconstrained · MANE · 4,033 bp · p 0.00084 · regional, not allelic
Overall
CADD	13.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 44% South Asian · 40,019/91,026 alleles

Filtering AF 43.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 43.5%

Overall 38.2% 615,174/1,611,094 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	46.4%	2
South Asiangrpmax	44%	2
European (non-Finnish)	39.7%	3
Remaining individualsnot grpmax-eligible	37.4%	3
Finnishnot grpmax-eligible	37.2%	3
East Asian	36.8%	3
Ashkenazi Jewishnot grpmax-eligible	36.1%	3
Admixed American	30.2%	3
Middle Eastern	29%	3
African / African-American	17.1%	6

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gly48Ser
Coding: c.142G>A
MANE Select: NM_003586
dbSNP: rs1140239
Type: single nucleotide variant
Location: chr16:30010081 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 1 PDB
Residue 48: a UniProt-annotated variant site (in); 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.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
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-gly48ser (accessed [today's date]).

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