Is ESS2 p.Arg175Gln (c.524G>A) pathogenic?

ESS2 p.Arg175Gln (c.524G>A) is classified Uncertain significance in ESS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-02). AlphaMissense: likely benign (0.0861); Ultra-rare (popmax 0.033%, mid).

How common is ESS2 p.Arg175Gln (c.524G>A) in the general population?

ESS2 p.Arg175Gln (c.524G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about ESS2 p.Arg175Gln (c.524G>A)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

ESS2 p.Arg175Gln

c.524G>A · rs200671779 · VCV2590919

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -10.55	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 10 kb · p 0.16 · regional, not allelic
Overall
CADD	25.0	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.02%

Overall 0.0206% 332/1,614,170 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,278
Remaining individualsnot grpmax-eligible	0.0368%	2,718
Middle Easterngrpmax	0.033%	3,031
Admixed American	0.0233%	4,288
European (non-Finnish)	0.0231%	4,322
African / African-American	0.00533%	18,758
South Asian	0.0022%	45,542
Finnishnot grpmax-eligible	0.00156%	64,026

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg175Gln
Coding: c.524G>A
MANE Select: NM_022719
dbSNP: rs200671779
Type: single nucleotide variant
Location: chr22:19139901 (GRCh38)
Gene constraint: LOEUF 0.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.41 · 5 PDB
Residue 175: an α-helix

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

Similar variants

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
ESS2 p.Ala115Gly 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/ess2-p-arg175gln (accessed [today's date]).

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