Is ESYT2 p.Pro503Ala (c.1507C>G) pathogenic?

ESYT2 p.Pro503Ala (c.1507C>G) is classified Uncertain significance in ESYT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely pathogenic (0.7095); Ultra-rare (popmax 0.0658%, mid).

How common is ESYT2 p.Pro503Ala (c.1507C>G) in the general population?

ESYT2 p.Pro503Ala (c.1507C>G) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

What do computational predictors say about ESYT2 p.Pro503Ala (c.1507C>G)?

AlphaMissense predicts likely pathogenic (score 0.7095) — an in-silico prediction, not a clinical call.

ESYT2 p.Pro503Ala

c.1507C>G · rs1239700982 · VCV3090650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7095 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7095	likely pathogenic
REVEL	0.618	indeterminate
SaProt	LLR -11.84	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 95 kb · p 0.024 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 P558A vs ClinVar P503A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0658% Middle Eastern · 4/6,082 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.000496% 8/1,613,538 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0658%	1,521
Admixed American	0.00167%	59,906
African / African-American	0.00134%	74,832
European (non-Finnish)	0.00017%	589,936

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.Pro503Ala
Coding: c.1507C>G
MANE Select: NM_001367773
dbSNP: rs1239700982
Type: single nucleotide variant
Location: chr7:158749699 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.44 · 4 PDB
Residue 503: a β-strand

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-pro503ala (accessed [today's date]).

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