Is SYN2 p.Pro501Leu (c.1502C>T) pathogenic?

SYN2 p.Pro501Leu (c.1502C>T) is classified Uncertain significance in SYN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: likely benign (0.0884); Ultra-rare (popmax 0.0107%, sas).

How common is SYN2 p.Pro501Leu (c.1502C>T) in the general population?

SYN2 p.Pro501Leu (c.1502C>T) is ultra-rare (popmax 0.0107%, sas) (gnomAD).

What do computational predictors say about SYN2 p.Pro501Leu (c.1502C>T)?

AlphaMissense predicts likely benign (score 0.0884) — an in-silico prediction, not a clinical call.

SYN2 p.Pro501Leu

c.1502C>T · rs558289553 · VCV2593554

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0884 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0884	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -2.2, phastCons 0.004
Regional constraint	o/e 1.02	unconstrained · MANE · 186 kb · p 0.66 · regional, not allelic
Overall
CADD	20.4	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 0.0107% South Asian · 9/84,252 alleles

Filtering AF 0.00551% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00413%

Overall 0.00167% 26/1,553,902 alleles · ultra-rare exomes 23/1,401,620 · genomes 3/152,282 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0107%	9,361
Admixed American	0.00782%	12,794
African / African-American	0.00409%	24,420
Remaining individualsnot grpmax-eligible	0.00166%	60,330
European (non-Finnish)	0.000784%	127,549

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: SYN2
Protein: p.Pro501Leu
Coding: c.1502C>T
MANE Select: NM_133625
dbSNP: rs558289553
Type: single nucleotide variant
Location: chr3:12187501 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 75.24
Residue 501: the 'disordered' region; the 'h; pro/ser-rich linker' region

Full SYN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SYN2 p.Ala54Val Benign ★★ same type
SYN2 p.Thr506Ala Benign ★★ same type
SYN2 c.1369+21G>C Uncertain significance ★ same type
SYN2 p.Ala302Gly Uncertain significance ★ same type
SYN2 p.Ala546Gly Uncertain significance ★ ⚠ same type
SYN2 p.Arg179Gln Uncertain significance ★ ⚠ same type
SYN2 p.Arg186Gln Uncertain significance ★ ⚠ same type
SYN2 p.Arg315Trp 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/syn2-p-pro501leu (accessed [today's date]).

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