Is INSYN2A p.Pro20Ser (c.58C>T) pathogenic?

INSYN2A p.Pro20Ser (c.58C>T) is classified Likely benign in INSYN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1303); Very rare (popmax 0.000169%, nfe).

How common is INSYN2A p.Pro20Ser (c.58C>T) in the general population?

INSYN2A p.Pro20Ser (c.58C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about INSYN2A p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely benign (score 0.1303) — an in-silico prediction, not a clinical call.

INSYN2A p.Pro20Ser

c.58C>T · VCV4679041

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1303 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

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	0.1303	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -5.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.1	phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 1,029 bp · p 0.63 · regional, not allelic
Overall
CADD	16.61	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 0.000169% European (non-Finnish) · 2/1,179,980 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,848 alleles · very rare exomes 2/1,461,592 · genomes 0/152,256 · joint denominator

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: INSYN2A
Protein: p.Pro20Ser
Coding: c.58C>T
MANE Select: NM_001039762
Type: single nucleotide variant
Location: chr10:127176338 (GRCh38)

Full INSYN2A 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/insyn2a-p-pro20ser (accessed [today's date]).

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