Is ELL2 p.Pro367Ala (c.1099C>G) pathogenic?

ELL2 p.Pro367Ala (c.1099C>G) is classified Uncertain significance in ELL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely benign (0.0561); Ultra-rare (popmax 0.0992%, mid).

How common is ELL2 p.Pro367Ala (c.1099C>G) in the general population?

ELL2 p.Pro367Ala (c.1099C>G) is ultra-rare (popmax 0.0992%, mid) (gnomAD).

What do computational predictors say about ELL2 p.Pro367Ala (c.1099C>G)?

AlphaMissense predicts likely benign (score 0.0561) — an in-silico prediction, not a clinical call.

ELL2 p.Pro367Ala

c.1099C>G · VCV4248329

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0561 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0992%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0561	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -6.09	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 4.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 73 kb · p 8e-16 · regional, not allelic
Overall
CADD	20.9	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 0.0992% Middle Eastern · 6/6,050 alleles

Filtering AF 0.0432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0295%

Overall 0.00298% 48/1,613,132 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0992%	1,008
South Asian	0.0077%	12,989
Admixed American	0.00667%	14,986
Remaining individualsnot grpmax-eligible	0.0032%	31,227
European (non-Finnish)	0.00246%	40,670

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.Pro367Ala
Coding: c.1099C>G
MANE Select: NM_012081
Type: single nucleotide variant
Location: chr5:95898666 (GRCh38)
Gene constraint: LOEUF 0.348 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.83 · 4 PDB
Residue 367: the 'disordered' region

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

Similar variants

ELL2 p.Pro367Ser Uncertain significance ★ ⚠ same residue
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

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-pro367ala (accessed [today's date]).

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