Is INSYN2B p.Ser263Arg (c.789C>A) pathogenic?

INSYN2B p.Ser263Arg (c.789C>A) is classified Uncertain significance in INSYN2B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-20). AlphaMissense: likely benign (0.1949); Ultra-rare (popmax 0.0833%, sas).

How common is INSYN2B p.Ser263Arg (c.789C>A) in the general population?

INSYN2B p.Ser263Arg (c.789C>A) is ultra-rare (popmax 0.0833%, sas) (gnomAD).

What do computational predictors say about INSYN2B p.Ser263Arg (c.789C>A)?

AlphaMissense predicts likely benign (score 0.1949) — an in-silico prediction, not a clinical call.

INSYN2B p.Ser263Arg

c.789C>A · rs370562223 · VCV3110020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1949 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0833%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1949	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -7.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.3	GERP -0.74
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.13 · regional, not allelic
Overall
CADD	13.71	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0833% South Asian · 70/84,060 alleles

Filtering AF 0.0675% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0618%

Overall 0.00683% 106/1,551,666 alleles · ultra-rare exomes 92/1,399,360 · genomes 14/152,306 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0833%	1,201
Remaining individualsnot grpmax-eligible	0.00998%	10,019
European (non-Finnish)	0.00253%	39,550
African / African-American	0.00137%	73,154

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: INSYN2B
Protein: p.Ser263Arg
Coding: c.789C>A
MANE Select: NM_001129891
dbSNP: rs370562223
Type: single nucleotide variant
Location: chr5:169883110 (GRCh38)

Full INSYN2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/insyn2b-p-ser263arg (accessed [today's date]).

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