Is STX3 p.Ser285Pro (c.853T>C) pathogenic?

STX3 p.Ser285Pro (c.853T>C) is classified Benign in STX3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-21). AlphaMissense: ambiguous (0.5296); Low-frequency (popmax 1.85%, afr).

How common is STX3 p.Ser285Pro (c.853T>C) in the general population?

STX3 p.Ser285Pro (c.853T>C) is low-frequency (popmax 1.85%, afr) (gnomAD).

What do computational predictors say about STX3 p.Ser285Pro (c.853T>C)?

AlphaMissense predicts ambiguous (score 0.5296) — an in-silico prediction, not a clinical call.

STX3 p.Ser285Pro

c.853T>C · rs34753750 · VCV770601

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5296 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.85%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5296	ambiguous
REVEL	0.218	benign-leaning
SaProt	LLR -15.57	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.04	GERP -3.1, phastCons 0.9
Regional constraint	o/e 0.99	unconstrained · MANE · 42 kb · p 0.89 · regional, not allelic
Overall
CADD	16.87	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 1.85% African / African-American · 1,390/75,036 alleles

Filtering AF 1.77% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.74%

Overall 0.105% 1,700/1,614,186 alleles · low-frequency exomes 851/1,461,866 · genomes 849/152,320 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.85%	54
Remaining individualsnot grpmax-eligible	0.133%	753
Admixed American	0.11%	909
Middle Eastern	0.099%	1,010
European (non-Finnish)	0.0126%	7,920
South Asian	0.00659%	15,181

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: STX3
Protein: p.Ser285Pro
Coding: c.853T>C
MANE Select: NM_004177
dbSNP: rs34753750
Type: single nucleotide variant
Location: chr11:59797349 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.60
Residue 285: a UniProt-annotated variant site (in diar12; loss of expression); a UniProt-annotated variant site (in)

Full STX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

STX3 p.Ser285= Likely benign ★ same residue
STX3 p.Arg247Ter Pathogenic ★★ same type
STX3 p.Ala10Val Uncertain significance ★★ ⚠ same type
STX3 p.Ala219Pro Uncertain significance ★★ ⚠ same type
STX3 p.Ala279Thr Uncertain significance ★★ ⚠ same type
STX3 p.Arg125Trp Uncertain significance ★★ ⚠ same type
STX3 p.Arg197Leu Uncertain significance ★★ ⚠ same type
STX3 p.Arg4Cys 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/stx3-p-ser285pro (accessed [today's date]).

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