Is STX3 p.Val91Phe (c.271G>T) pathogenic?

STX3 p.Val91Phe (c.271G>T) is classified Uncertain significance in STX3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-07). AlphaMissense: likely pathogenic (0.9052); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with STX3 p.Val91Phe (c.271G>T)?

STX3 p.Val91Phe (c.271G>T) is associated with Inborn genetic diseases (ClinVar).

How common is STX3 p.Val91Phe (c.271G>T) in the general population?

STX3 p.Val91Phe (c.271G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about STX3 p.Val91Phe (c.271G>T)?

AlphaMissense predicts likely pathogenic (score 0.9052) — an in-silico prediction, not a clinical call.

STX3 p.Val91Phe

c.271G>T · rs200311584 · VCV1463246

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9052 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9052	likely pathogenic
REVEL	0.258	benign-leaning
SaProt	LLR -12.40	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.77, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 42 kb · p 0.89 · regional, not allelic
Overall
CADD	27.1	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00273% 44/1,610,426 alleles · ultra-rare exomes 41/1,458,306 · genomes 3/152,120 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.105%	950
Middle Easterngrpmax	0.0165%	6,078
Remaining individualsnot grpmax-eligible	0.00802%	12,473
European (non-Finnish)	0.000594%	168,330

Ashkenazi Jewish 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: STX3
Protein: p.Val91Phe
Coding: c.271G>T
MANE Select: NM_004177
dbSNP: rs200311584
Type: single nucleotide variant
Location: chr11:59788929 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.60

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

STX3 p.Val91Ile Uncertain significance ★★ ⚠ same residue
STX3 p.Ala219Pro Uncertain significance ★★ ⚠ same condition
STX3 p.Ala279Thr Uncertain significance ★★ ⚠ same condition
STX3 p.Arg125Trp Uncertain significance ★★ ⚠ same condition
STX3 p.Arg197Leu Uncertain significance ★★ ⚠ same condition
STX3 p.Arg4Cys Uncertain significance ★★ ⚠ same condition
STX3 p.Arg92Gln Uncertain significance ★★ ⚠ same condition
STX3 p.Arg92Trp Uncertain significance ★★ ⚠ same condition

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-val91phe (accessed [today's date]).

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