Is ESS2 p.Glu165Asp (c.495G>T) pathogenic?

ESS2 p.Glu165Asp (c.495G>T) is classified Uncertain significance in ESS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.1755); Ultra-rare (popmax 0.07%, amr).

How common is ESS2 p.Glu165Asp (c.495G>T) in the general population?

ESS2 p.Glu165Asp (c.495G>T) is ultra-rare (popmax 0.07%, amr) (gnomAD).

What do computational predictors say about ESS2 p.Glu165Asp (c.495G>T)?

AlphaMissense predicts likely benign (score 0.1755) — an in-silico prediction, not a clinical call.

ESS2 p.Glu165Asp

c.495G>T · VCV4665438

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1755 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.07%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1755	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -9.09	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 2.2	GERP -2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 10 kb · p 0.16 · regional, not allelic
Overall
CADD	18.26	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 0.07% Admixed American · 42/60,010 alleles

Filtering AF 0.0532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0473%

Overall 0.00266% 43/1,614,088 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.07%	1,429
European (non-Finnish)	8.47e-05%	1,180,045

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.Glu165Asp
Coding: c.495G>T
MANE Select: NM_022719
Type: single nucleotide variant
Location: chr22:19139930 (GRCh38)
Gene constraint: LOEUF 0.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.41 · 5 PDB
Residue 165: an α-helix

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

Similar variants

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
ESS2 p.Ser7Ala Benign ★★ same type
ESS2 p.Thr460= Likely 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-glu165asp (accessed [today's date]).

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