Is DOC2A p.Val355Met (c.1063G>A) pathogenic?

DOC2A p.Val355Met (c.1063G>A) is classified Uncertain significance in DOC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: ambiguous (0.4982); Very rare (popmax 0.00669%, eas).

How common is DOC2A p.Val355Met (c.1063G>A) in the general population?

DOC2A p.Val355Met (c.1063G>A) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about DOC2A p.Val355Met (c.1063G>A)?

AlphaMissense predicts ambiguous (score 0.4982) — an in-silico prediction, not a clinical call.

DOC2A p.Val355Met

c.1063G>A · VCV4014007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Computational evidence

Protein change
AlphaMissense	0.4982	ambiguous
REVEL	0.463	indeterminate
SaProt	LLR -7.87	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.74, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 4,033 bp · p 0.00084 · regional, not allelic
Overall
CADD	23.8	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 0.00669% East Asian · 3/44,846 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00304% 49/1,611,844 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,949
African / African-American	0.00667%	14,993
Remaining individualsnot grpmax-eligible	0.0064%	15,613
European (non-Finnish)	0.00288%	34,696
South Asian	0.0022%	45,522
Admixed American	0.00167%	59,978

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.Val355Met
Coding: c.1063G>A
MANE Select: NM_003586
Type: single nucleotide variant
Location: chr16:30006326 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 1 PDB
Residue 355: the c2 2 domain; 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-val355met (accessed [today's date]).

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