Is ESS2 p.Pro387Arg (c.1160C>G) pathogenic?

ESS2 p.Pro387Arg (c.1160C>G) is classified Uncertain significance in ESS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely pathogenic (0.6776); Ultra-rare (popmax 0.0173%, mid).

How common is ESS2 p.Pro387Arg (c.1160C>G) in the general population?

ESS2 p.Pro387Arg (c.1160C>G) is ultra-rare (popmax 0.0173%, mid) (gnomAD).

What do computational predictors say about ESS2 p.Pro387Arg (c.1160C>G)?

AlphaMissense predicts likely pathogenic (score 0.6776) — an in-silico prediction, not a clinical call.

ESS2 p.Pro387Arg

c.1160C>G · VCV4019868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6776 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6776	likely pathogenic
REVEL	0.441	indeterminate
SaProt	LLR -9.66	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 10 kb · p 0.16 · regional, not allelic
Overall
CADD	28.6	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 0.0173% Middle Eastern · 1/5,794 alleles

Filtering AF 0.000513% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000375%

Overall 0.000896% 14/1,561,782 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0173%	5,794
Admixed American	0.00182%	54,850
Remaining individualsnot grpmax-eligible	0.00166%	60,076
European (non-Finnish)	0.000956%	104,573

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: ESS2
Protein: p.Pro387Arg
Coding: c.1160C>G
MANE Select: NM_022719
Type: single nucleotide variant
Location: chr22:19134467 (GRCh38)
Gene constraint: LOEUF 0.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.41 · 5 PDB

Full ESS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESS2 p.Pro387Leu Uncertain significance ★ ⚠ same residue
ESS2 p.Pro387Thr Uncertain significance ★ ⚠ same residue
ESS2 p.Arg175Gln Uncertain significance ★★ ⚠ same type
ESS2 p.Asn311= Benign ★★ same type
ESS2 p.Glu234Lys Benign ★★ ⚠ same type
ESS2 p.His178= Likely benign ★★ same type
ESS2 p.Lys66= Benign/Likely benign ★★ same type
ESS2 p.Pro99Leu Benign ★★ 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/ess2-p-pro387arg (accessed [today's date]).

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