Is ESS2 p.Arg415Trp (c.1243C>T) pathogenic?

ESS2 p.Arg415Trp (c.1243C>T) is classified Uncertain significance in ESS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-22). AlphaMissense: likely pathogenic (0.6638); Very rare (popmax 0.00517%, nfe).

How common is ESS2 p.Arg415Trp (c.1243C>T) in the general population?

ESS2 p.Arg415Trp (c.1243C>T) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about ESS2 p.Arg415Trp (c.1243C>T)?

AlphaMissense predicts likely pathogenic (score 0.6638) — an in-silico prediction, not a clinical call.

ESS2 p.Arg415Trp

c.1243C>T · rs377464869 · VCV3090587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6638	likely pathogenic
REVEL	0.361	indeterminate
SaProt	LLR -10.90	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.8	GERP 0.036, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 10 kb · p 0.16 · regional, not allelic
Overall
CADD	27.1	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00517% European (non-Finnish) · 61/1,179,056 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00434% 70/1,611,412 alleles · very rare exomes 62/1,459,112 · genomes 8/152,300 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00633%	15,796
European (non-Finnish)grpmax	0.00517%	19,329
African / African-American	0.004%	24,993
East Asian	0.00223%	44,744
South Asian	0.0011%	90,836

Finnish 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.Arg415Trp
Coding: c.1243C>T
MANE Select: NM_022719
dbSNP: rs377464869
Type: single nucleotide variant
Location: chr22:19134384 (GRCh38)
Gene constraint: LOEUF 0.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.41 · 5 PDB
Residue 415: the 'disordered' region

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-arg415trp (accessed [today's date]).

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