Is DOC2A p.Ser398Pro (c.1192T>C) pathogenic?

DOC2A p.Ser398Pro (c.1192T>C) is classified Likely benign in DOC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely benign (0.0454); Very rare (popmax 0.00182%, amr).

How common is DOC2A p.Ser398Pro (c.1192T>C) in the general population?

DOC2A p.Ser398Pro (c.1192T>C) is very rare (popmax 0.00182%, amr) (gnomAD).

What do computational predictors say about DOC2A p.Ser398Pro (c.1192T>C)?

AlphaMissense predicts likely benign (score 0.0454) — an in-silico prediction, not a clinical call.

DOC2A p.Ser398Pro

c.1192T>C · VCV4014009

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0454 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00182%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0454	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -5.60	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 2.8	GERP -1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 4,033 bp · p 0.00084 · regional, not allelic
Overall
CADD	7.519	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 0.00182% Admixed American · 1/54,880 alleles

Filtering AF 0.000622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000479%

Overall 0.000978% 14/1,432,058 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00182%	54,880
European (non-Finnish)	0.00111%	89,759

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.Ser398Pro
Coding: c.1192T>C
MANE Select: NM_003586
Type: single nucleotide variant
Location: chr16:30006197 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 1 PDB
Residue 398: 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.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-ser398pro (accessed [today's date]).

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