Is ELL2 p.Arg561Ser (c.1683G>C) pathogenic?

ELL2 p.Arg561Ser (c.1683G>C) is classified Uncertain significance in ELL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). AlphaMissense: likely pathogenic (0.8266); Very rare (popmax 0.000254%, nfe).

How common is ELL2 p.Arg561Ser (c.1683G>C) in the general population?

ELL2 p.Arg561Ser (c.1683G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ELL2 p.Arg561Ser (c.1683G>C)?

AlphaMissense predicts likely pathogenic (score 0.8266) — an in-silico prediction, not a clinical call.

ELL2 p.Arg561Ser

c.1683G>C · VCV3844453

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8266 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8266	likely pathogenic
REVEL	0.273	benign-leaning
SaProt	LLR -11.88	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -3.6, phastCons 0.36
Regional constraint	o/e 0.70	unconstrained · MANE · 73 kb · p 8e-16 · regional, not allelic
Overall
CADD	21.1	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 0.000254% European (non-Finnish) · 3/1,180,038 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,868 alleles · very rare

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: ELL2
Protein: p.Arg561Ser
Coding: c.1683G>C
MANE Select: NM_012081
Type: single nucleotide variant
Location: chr5:95891181 (GRCh38)
Gene constraint: LOEUF 0.348 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.83 · 4 PDB
Residue 561: the ocel domain; an α-helix

Full ELL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ELL2 p.Ile58Val Likely benign ★★ ⚠ same type
ELL2 p.Ala218Pro Uncertain significance ★ ⚠ same type
ELL2 p.Arg135Gln Uncertain significance ★ ⚠ same type
ELL2 p.Arg167Pro Uncertain significance ★ ⚠ same type
ELL2 p.Arg180Thr Uncertain significance ★ ⚠ same type
ELL2 p.Arg193Gln Uncertain significance ★ ⚠ same type
ELL2 p.Arg281Gln Uncertain significance ★ ⚠ same type
ELL2 p.Arg281Trp 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/ell2-p-arg561ser (accessed [today's date]).

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