Is ESYT2 p.Pro609Ser (c.1825C>T) pathogenic?

ESYT2 p.Pro609Ser (c.1825C>T) is classified Uncertain significance in ESYT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.0741); Ultra-rare (popmax 0.0136%, amr).

How common is ESYT2 p.Pro609Ser (c.1825C>T) in the general population?

ESYT2 p.Pro609Ser (c.1825C>T) is ultra-rare (popmax 0.0136%, amr) (gnomAD).

What do computational predictors say about ESYT2 p.Pro609Ser (c.1825C>T)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

ESYT2 p.Pro609Ser

c.1825C>T · VCV4019899

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0741	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -5.94	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 2.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 95 kb · p 0.024 · regional, not allelic
Overall
CADD	13.05	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P664S vs ClinVar P609S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0136% Admixed American · 8/58,948 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.000621% 10/1,609,816 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0136%	7,368
European (non-Finnish)	0.00017%	589,202

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: ESYT2
Protein: p.Pro609Ser
Coding: c.1825C>T
MANE Select: NM_001367773
Type: single nucleotide variant
Location: chr7:158741866 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.44 · 4 PDB
Residue 609: the c2 2 domain; a turn

Full ESYT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESYT2 c.26C>T Uncertain significance ★ same type
ESYT2 c.43C>G Uncertain significance ★ same type
ESYT2 c.-17C>G Uncertain significance ★ same type
ESYT2 c.-38C>T Uncertain significance ★ ⚠ same type
ESYT2 c.-41A>C Uncertain significance ★ ⚠ same type
ESYT2 c.-55C>G Uncertain significance ★ same type
ESYT2 c.-59G>A Uncertain significance ★ ⚠ same type
ESYT2 c.-62C>G 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/esyt2-p-pro609ser (accessed [today's date]).

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