Is ESS2 p.Arg412Trp (c.1234C>T) pathogenic?

ESS2 p.Arg412Trp (c.1234C>T) is classified Uncertain significance in ESS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-03). AlphaMissense: ambiguous (0.3966); Ultra-rare (popmax 0.0385%, amr).

How common is ESS2 p.Arg412Trp (c.1234C>T) in the general population?

ESS2 p.Arg412Trp (c.1234C>T) is ultra-rare (popmax 0.0385%, amr) (gnomAD).

What do computational predictors say about ESS2 p.Arg412Trp (c.1234C>T)?

AlphaMissense predicts ambiguous (score 0.3966) — an in-silico prediction, not a clinical call.

ESS2 p.Arg412Trp

c.1234C>T · rs186717850 · VCV3090586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3966 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0385%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3966	ambiguous
REVEL	0.148	moderately benign-leaning
SaProt	LLR -11.03	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 10 kb · p 0.16 · regional, not allelic
Overall
CADD	34.0	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 0.0385% Admixed American · 23/59,778 alleles

Filtering AF 0.0262% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.0023% 37/1,611,506 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0385%	2,599
Middle Eastern	0.0165%	6,048
European (non-Finnish)	0.0011%	90,688

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.Arg412Trp
Coding: c.1234C>T
MANE Select: NM_022719
dbSNP: rs186717850
Type: single nucleotide variant
Location: chr22:19134393 (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.Arg412Gln 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
ESS2 p.Ser7Ala 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-arg412trp (accessed [today's date]).

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